# gene_set

collection_name: C3:MIR:MIR_LEGACY
license_code: CC-BY-4.0
standard_name:
  AGCACTT_MIR93_MIR302A_MIR302B_MIR302C_MIR302D_MIR372_MIR373_MIR520E_MIR520A_MIR526B_MIR520B_MIR520C_MIR520D


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_NEF_MEDIATES_DOWN_MODULATION_OF_CELL_SURFACE_RECEPTORS_BY_RECRUITING_THEM_TO_CLATHRIN_ADAPTERS


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_REGULATION_OF_GENE_EXPRESSION_IN_LATE_STAGE_BRANCHING_MORPHOGENESIS_PANCREATIC_BUD_PRECURSOR_CELLS


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_REGULATION_OF_INSULIN_LIKE_GROWTH_FACTOR_IGF_TRANSPORT_AND_UPTAKE_BY_INSULIN_LIKE_GROWTH_FACTOR_BINDING_PROTEINS_IGFBPS


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_BIOSYNTHESIS_OF_THE_N_GLYCAN_PRECURSOR_DOLICHOL_LIPID_LINKED_OLIGOSACCHARIDE_LLO_AND_TRANSFER_TO_A_NASCENT_PROTEIN


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_ACTIVATED_PKN1_STIMULATES_TRANSCRIPTION_OF_AR_ANDROGEN_RECEPTOR_REGULATED_GENES_KLK2_AND_KLK3


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_TP53_REGULATES_TRANSCRIPTION_OF_SEVERAL_ADDITIONAL_CELL_DEATH_GENES_WHOSE_SPECIFIC_ROLES_IN_P53_DEPENDENT_APOPTOSIS_REMAIN_UNCERTAIN


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_TP53_REGULATES_TRANSCRIPTION_OF_ADDITIONAL_CELL_CYCLE_GENES_WHOSE_EXACT_ROLE_IN_THE_P53_PATHWAY_REMAIN_UNCERTAIN


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_ACTIVATION_OF_THE_MRNA_UPON_BINDING_OF_THE_CAP_BINDING_COMPLEX_AND_EIFS_AND_SUBSEQUENT_BINDING_TO_43S


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_TFAP2A_ACTS_AS_A_TRANSCRIPTIONAL_REPRESSOR_DURING_RETINOIC_ACID_INDUCED_CELL_DIFFERENTIATION


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_PBMC_ZOSTAVAX_AGE_50_75YO_CORRELATED_WITH_CONTRACTION_OF_VZV_SPECIFIC_T_CELLS_PEAK_TO_28DY_AT_1DYPOSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_PBMC_ZOSTAVAX_AGE_50_75YO_CORRELATED_WITH_EXPANSION_OF_VZV_SPECIFIC_T_CELLS_TO_PEAK_AT_1DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_FLUARIX_AGE_50_74YO_CORR_WITH_28D_MEM_B_CELL_RESPONSE_AT_28DY_LEUK_MIGR_MAPK_ACT_CYTOK_SIG_DIAB_OF_THE_YNG_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_PBMC_ZOSTAVAX_AGE_50_75YO_CORRELATED_WITH_EXPANSION_OF_VZV_SPECIFIC_T_CELLS_TO_PEAK_AT_1DY_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_0DY_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_PBMC_ZOSTAVAX_AGE_50_75YO_CORRELATED_WITH_CONTRACTION_OF_VZV_SPECIFIC_T_CELLS_PEAK_TO_28DYAT_1DY_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOFT_CD4_POSITIVE_ALPHA_BETA_MEMORY_T_CELL_BCG_VACCINE_AGE_18_45YO_56D_TOP_100_DEG_AFTER_IN_VITRO_RE_STIMULATION_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_M_M_R_II_AGE_11_22YO_VACCINATED_VS_UNVACCINATED_LOW_ANTIBODY_RESPONDERS_TO_TREATMENT_7YR_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  WEINBERGER_BLOOD_TWINRIX_AGE_20_40_AND_60_84YO_CORRELATED_WITH_HIGH_ANTI_HBS_CONC_AT_WEEK_4_POST_BOOSTER_VACC_1DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  ERWIN_COHEN_PBMC_TC_83_AGE_18_45YO_NON_RESPONDERS_PREVIOUSLY_IMMUNIZED_24HR_DEG_CANONICAL_PATHWAY_MEMBERS_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOWARD_PBMC_INACT_MONOV_INFLUENZA_A_INDONESIA_05_2005_H5N1_AGE_19_39YO_AS03_ADJUVANT_VS_BUFFER_1DY_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_14DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_PBMC_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_18_55YO_VACCINATED_VS_CONTROL_TREATED_IN_VITRO_WITH_MVA85A_6HR_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_M_M_R_II_AGE_11_22YO_VACCINATED_VS_UNVACCINATED_HIGH_ANTIBODY_RESPONDERS_TO_TREATMENT_7YR_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_PBMC_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_18_55YO_HIGH_RESPONDERS_VS_LOW_RESPONDERS_0DY_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  NAKAYA_PBMC_FLUAD_MALE_AGE_14_27YO_1D_POSTBOOST_VS_0D_PREIMM_MF59_ADJUVANTED_1DY_GENES_IN_BTM_M40_AND_M53_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  WEINBERGER_BLOOD_TWINRIX_AGE_20_40_AND_60_84YO_CORRELATED_WITH_HIGH_ANTI_HBS_CONC_AT_WEEK_30_PRIMARY_VACC_1DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_PBMC_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_18_55YO_LOW_VS_HIGH_RESPONDERS_2DY_GO_T_CELL_ACTIV_AND_CO_STIM_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_BLOOD_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_4_6MO_VACCINATED_VS_CANDIN_PLACEBO_BCG_PRIMED_1DY_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  PATEL_SKIN_OF_BODY_ZOSTAVAX_AGE_70_93YO_VZV_CHALLENGED_POST_VACCINATION_VS_UNCHALLENGED_72HR_TOP_30_DEG_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_PBMC_ZOSTAVAX_AGE_50_75YO_CORRELATED_WITH_T_CELL_RESPONSES_EXPANSION_AND_CONTRACTION_1D_NOT_INFORMATIVE_OF_LONG_TERM_RESPONSES_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  ERWIN_COHEN_PBMC_TC_83_AGE_18_45YO_NON_RESPONDERS_PREVIOUSLY_IMMUNIZED_24HR_DEG_CANONICAL_PATHWAY_MEMBERS_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  BUCASAS_PBMC_FLUARIX_FLUVIRIN_CAUCASIAN_MALE_AGE_18_40YO_LOW_RESPONDERS_1DY_POSITIVE_PREDICTIVE_OF_TITER


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  OVSYANNIKOVA_PBMC_FLUARIX_AGE_50_74YO_COMMON_WITH_BOTH_HAI_AND_VNA_28DY_VS_3DY_USED_IN_HAI_AND_VNA_RESPONSE_MODELS_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_PBMC_ZOSTAVAX_AGE_50_75YO_CORRELATED_WITH_T_CELL_RESPONSES_1D_INFORMATIVE_OF_LONG_TERM_RESPONSES_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_BLOOD_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_4_6MO_VACCINATED_VS_CANDIN_PLACEBO_BCG_PRIMED_1DY_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_1DY_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOWARD_PBMC_INACT_MONOV_INFLUENZA_A_INDONESIA_05_2005_H5N1_AGE_19_39YO_AS03_ADJUVANT_VS_BUFFER_1DY_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  NAKAYA_PBMC_FLUAD_IMUVAC_MALE_AGE_14_27YO_CORRELATED_WITH_HAI_RESPONSE_MF59_ADJUVANTED_AND_NON_1DY_GENES_IN_BTM_M75_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FOURATI_BLOOD_TWINRIX_AGE_65_81YO_RESPONDERS_VS_POOR_RESPONDERS_TRAINING_SET_0DY_NETWORK_INFERENCE_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  KAZMIN_PBMC_P_FALCIPARUM_RTSS_AS01_UNKN_AGE_IMM_WITH_ARR_VS_IMM_BY_RRR_PRIMARY_IMMUNIZ_WITH_RECOMB_ADENOVIRUS_35_1DY_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  GARCIA_PINERES_PBMC_HPV_16_L1_VLP_AGE_18_25YO_STIMULATED_VS_UNSTIMULATED_0DY_VACCINATION_INDEPENDENT_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOFT_PBMC_TICE_BCG_RBCG_AG85A_AG85B_AGE_18_40YO_CORRELATED_WITH_WHOLE_BLOOD_BACTERICIDAL_ACTIVITY_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_3DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_0DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  BUCASAS_PBMC_FLUARIX_FLUVIRIN_CAUCASIAN_MALE_AGE_18_40YO_HIGH_RESPONDERS_1DY_TOP_FUNCTIONAL_NETWORK_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  SOBOLEV_PBMC_PANDEMRIX_AGE_18_64YO_HIGH_VS_LOW_RESPONDERS_MEDIUM_HIGH_ADVERSE_EVENTS_SCORE_1DY_TRANSIENT_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  OVSYANNIKOVA_PBMC_FLUARIX_AGE_50_74YO_COMMON_WITH_BOTH_HAI_AND_VNA_28DY_VS_3DY_USED_IN_HAI_AND_VNA_RESPONSE_MODELS_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  OVSYANNIKOVA_PBMC_FLUARIX_AGE_50_74YO_COMMON_WITH_BOTH_HAI_AND_VNA_28DY_VS_0DY_USED_IN_HAI_AND_VNA_RESPONSE_MODELS_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_14DY_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_FLUARIX_AGE_50_74YO_CORR_WITH_28D_MEM_B_CELL_RESPONSE_AT_28DY_LATE_GENE_EXPR_INDIVID_GENE_MODELS_PRED_PEAK_B_CELL_ELISPOT_RESP_NEGATIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  ERWIN_COHEN_PBMC_TC_83_AGE_18_45YO_RESPONDERS_PREVIOUSLY_IMMUNIZED_24HR_DEG_CANONICAL_PATHWAY_MEMBERS_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  ERWIN_COHEN_PBMC_TC_83_AGE_18_45YO_NAIVE_NOT_PREVIOUSLY_IMMUNIZED_24HR_DEG_CANONICAL_PATHWAY_MEMBERS_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  NAKAYA_PBMC_FLUAD_MALE_AGE_14_27YO_1D_POSTBOOST_VS_0D_PREIMM_MF59_ADJUVANTED_1DY_GENES_IN_BTM_M40_AND_M53_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FRANCO_BLOOD_SANOFI_PASTEUR_SA_INACTIVATED_INFLUENZA_VACCINE_CORRELATED_WITH_ANTIBODY_RESPONSE_AGE_18_40YO_1DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_M_M_R_II_AGE_11_22YO_VACCINATED_VS_UNVACCINATED_LOW_ANTIBODY_RESPONDERS_TO_TREATMENT_7YR_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HIPC_SIGNATURES_PROJECT_PBMC_TRIVALENT_INFLUENZA_VACCINE_HIGH_RESPONDERS_VS_LOW_RESPONDERS_YOUNGER_ADULTS_21_35_HIGH_RESPONDERS_0D_DOWN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HIPC_SIGNATURES_PROJECT_PBMC_TRIVALENT_INFLUENZA_VACCINE_HIGH_RESPONDERS_VS_LOW_RESPONDERS_YOUNGER_ADULTS_21_35_HIGH_RESPONDERS_0D_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_FLUARIX_AGE_50_74YO_CORR_WITH_28D_MEM_B_CELL_RESPONSE_AT_28DY_LATE_GENE_EXPR_INDIVID_GENE_MODELS_PRED_PEAK_B_CELL_ELISPOT_RESP_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  GARCIA_PINERES_PBMC_HPV_16_L1_VLP_AGE_18_25YO_STIMULATED_VS_UNSTIMULATED_0DY_VACCINATION_INDEPENDENT_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOFT_CD4_POSITIVE_ALPHA_BETA_MEMORY_T_CELL_BCG_VACCINE_AGE_18_45YO_56D_TOP_100_DEG_AFTER_IN_VITRO_RE_STIMULATION_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  WEINBERGER_BLOOD_TWINRIX_AGE_20_40_AND_60_84YO_CORRELATED_WITH_ANTI_HBS_CONC_PRIMARY_VACC_1DY_SIGNIFICANT


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  FOURATI_BLOOD_TWINRIX_AGE_65_81Y0_RESPONDERS_VS_POOR_RESPONDERS_TRAINING_SET_0DY_NETWORK_INFERENCE_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_PBMC_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_4_6MO_VACCINATED_VS_CANDIN_PLACEBO_BCG_PRIMED_28DY_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  BUCASAS_PBMC_FLUARIX_FLUVIRIN_CAUCASIAN_MALE_AGE_18_40YO_HIGH_RESPONDERS_1DY_3DY_POSITIVE_PREDICTIVE_OF_TITER


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  OVSYANNIKOVA_PBMC_FLUARIX_AGE_50_74YO_COMMON_WITH_BOTH_HAI_AND_VNA_28DY_VS_0DY_USED_IN_HAI_AND_VNA_RESPONSE_MODELS_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HARALAMBIEVA_PBMC_FLUARIX_AGE_50_74YO_CORR_WITH_28D_MEM_B_CELL_RESPONSE_AT_28DY_LEUK_MIGR_MAPK_ACT_CYTOK_SIG_DIAB_OF_THE_YNG_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOFT_CD4_POSITIVE_ALPHA_BETA_MEMORY_T_CELL_BCG_VACCINE_AGE_18_45YO_ID_56D_TOP_100_DEG_AFTER_IN_VITRO_RE_STIMULATION_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  HOFT_CD4_POSITIVE_ALPHA_BETA_MEMORY_T_CELL_BCG_VACCINE_AGE_18_45YO_ID_56D_TOP_100_DEG_AFTER_IN_VITRO_RE_STIMULATION_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  QI_CD4_POSITIVE_ALPHA_BETA_MEMORY_T_CELL_ZOSTAVAX_AGE_52_75YO_CD4_T_CELL_VS_NAIVE_CD4_T_CELL_7_TO_9DY_DN


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  MATSUMIYA_PBMC_MODIFIED_VACCINIA_ANKARA_VACCINE_AGE_18_55YO_VACCINATED_VS_CONTROL_TREATED_IN_VITRO_WITH_WILD_TYPE_MVA_6HR_UP


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  TSANG_PBMC_FLUVIRIN_PANDEMRIX_ADULT_CORR_WITH_CELL_FREQ_CD27HI_CD38HI_CD20_NEG_PLASMABLASTS_AND_CD38PLUS_OF_IGD_CD27PLUS_MEM_B_CELLS_7DY_POSITIVE


collection_name: C7:VAX
license_code: CC-BY-4.0
standard_name:
  SOBOLEV_PBMC_PANDEMRIX_AGE_18_64YO_HIGH_VS_LOW_RESPONDERS_MEDIUM_HIGH_ADVERSE_EVENTS_SCORE_1DY_CORRELATED_WITH_TRANSITIONAL_B_CELLS_UP


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_ENDONUCLEOLYTIC_CLEAVAGE_IN_ITS1_TO_SEPARATE_SSU_RRNA_FROM_5_8S_RRNA_AND_LSU_RRNA_FROM_TRICISTRONIC_RRNA_TRANSCRIPT_SSU_RRNA_5_8S_RRNA_LSU_RRNA


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_RENAL_RESPONSE_TO_BLOOD_FLOW_INVOLVED_IN_CIRCULATORY_RENIN_ANGIOTENSIN_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_T_CELL_ACTIVATION_VIA_T_CELL_RECEPTOR_CONTACT_WITH_ANTIGEN_BOUND_TO_MHC_MOLECULE_ON_ANTIGEN_PRESENTING_CELL


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_ADAPTIVE_IMMUNE_RESPONSE_BASED_ON_SOMATIC_RECOMBINATION_OF_IMMUNE_RECEPTORS_BUILT_FROM_IMMUNOGLOBULIN_SUPERFAMILY_DOMAINS


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_RENAL_CONTROL_OF_PERIPHERAL_VASCULAR_RESISTANCE_INVOLVED_IN_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_ACTIVATION_OF_CYSTEINE_TYPE_ENDOPEPTIDASE_ACTIVITY_INVOLVED_IN_APOPTOTIC_PROCESS_BY_CYTOCHROME_C


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_REGULATION_OF_THE_RELEASE_OF_SEQUESTERED_CALCIUM_ION


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_MODULATION_OF_MICROTUBULE_CYTOSKELETON_INVOLVED_IN_CEREBRAL_CORTEX_RADIAL_GLIA_GUIDED_MIGRATION


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_PROTEIN_TRANSPORT_TO_VACUOLE_INVOLVED_IN_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS_VIA_THE_MULTIVESICULAR_BODY_SORTING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_SINGLE_STRANDED_VIRAL_RNA_REPLICATION_VIA_DOUBLE_STRANDED_DNA_INTERMEDIATE


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_NUCLEAR_TRANSCRIBED_MRNA_CATABOLIC_PROCESS_DEADENYLATION_DEPENDENT_DECAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_NUCLEAR_TRANSCRIBED_MRNA_CATABOLIC_PROCESS_DEADENYLATION_DEPENDENT_DECAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_MITOCHONDRIAL_OUTER_MEMBRANE_PERMEABILIZATION_INVOLVED_IN_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_MITOCHONDRIAL_OUTER_MEMBRANE_PERMEABILIZATION_INVOLVED_IN_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_OUTER_MEMBRANE_PERMEABILIZATION_INVOLVED_IN_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR_RESULTING_IN_TRANSCRIPTION_OF_P21_CLASS_MEDIATOR


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR_RESULTING_IN_TRANSCRIPTION_OF_P21_CLASS_MEDIATOR


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_ENDOPLASMIC_RETICULUM_STRESS_INDUCED_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_ENDOPLASMIC_RETICULUM_STRESS_INDUCED_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_ASPARTIC_TYPE_ENDOPEPTIDASE_ACTIVITY_INVOLVED_IN_AMYLOID_PRECURSOR_PROTEIN_CATABOLIC_PROCESS


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_ASPARTIC_TYPE_ENDOPEPTIDASE_ACTIVITY_INVOLVED_IN_AMYLOID_PRECURSOR_PROTEIN_CATABOLIC_PROCESS


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_PROLIFERATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_PROLIFERATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT_VIA_HIGH_VOLTAGE_GATED_CALCIUM_CHANNEL


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_REGULATION_OF_T_CELL_ACTIVATION_VIA_T_CELL_RECEPTOR_CONTACT_WITH_ANTIGEN_BOUND_TO_MHC_MOLECULE_ON_ANTIGEN_PRESENTING_CELL


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_NEGATIVE_REGULATION_OF_CYSTEINE_TYPE_ENDOPEPTIDASE_ACTIVITY_INVOLVED_IN_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:BP
license_code: CC-BY-4.0
standard_name:
  GOBP_POSITIVE_REGULATION_OF_CYSTEINE_TYPE_ENDOPEPTIDASE_ACTIVITY_INVOLVED_IN_APOPTOTIC_SIGNALING_PATHWAY


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_NAD_P_H_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_REDUCED_FLAVIN_OR_FLAVOPROTEIN_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_REDUCED_IRON_SULFUR_PROTEIN_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_REDUCED_PTERIDINE_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_REDUCED_ASCORBATE_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN_ANOTHER_COMPOUND_AS_ONE_DONOR_AND_INCORPORATION_OF_ONE_ATOM_OF_OXYGEN


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_OXIDATION_OF_A_PAIR_OF_DONORS_RESULTING_IN_THE_REDUCTION_OF_MOLECULAR_OXYGEN_TO_TWO_MOLECULES_OF_WATER


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_EXONUCLEASE_ACTIVITY_ACTIVE_WITH_EITHER_RIBO_OR_DEOXYRIBONUCLEIC_ACIDS_AND_PRODUCING_5_PHOSPHOMONOESTERS


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_ENDONUCLEASE_ACTIVITY_ACTIVE_WITH_EITHER_RIBO_OR_DEOXYRIBONUCLEIC_ACIDS_AND_PRODUCING_5_PHOSPHOMONOESTERS


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_ENDONUCLEASE_ACTIVITY_ACTIVE_WITH_EITHER_RIBO_OR_DEOXYRIBONUCLEIC_ACIDS_AND_PRODUCING_3_PHOSPHOMONOESTERS


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_GLUCURONOSYL_N_ACETYLGALACTOSAMINYL_PROTEOGLYCAN_4_BETA_N_ACETYLGALACTOSAMINYLTRANSFERASE_ACTIVITY


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_VOLTAGE_GATED_POTASSIUM_CHANNEL_ACTIVITY_INVOLVED_IN_CARDIAC_MUSCLE_CELL_ACTION_POTENTIAL_REPOLARIZATION


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_LIGAND_GATED_MONOATOMIC_ION_CHANNEL_ACTIVITY_INVOLVED_IN_REGULATION_OF_PRESYNAPTIC_MEMBRANE_POTENTIAL


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_VOLTAGE_GATED_MONOATOMIC_ION_CHANNEL_ACTIVITY_INVOLVED_IN_REGULATION_OF_PRESYNAPTIC_MEMBRANE_POTENTIAL


collection_name: C5:GO:MF
license_code: CC-BY-4.0
standard_name:
  GOMF_VOLTAGE_GATED_POTASSIUM_CHANNEL_ACTIVITY_INVOLVED_IN_VENTRICULAR_CARDIAC_MUSCLE_CELL_ACTION_POTENTIAL_REPOLARIZATION


collection_name: C5:HPO
license_code: CC-BY-4.0
standard_name:
  HP_COMPLETE_OR_NEAR_COMPLETE_ABSENCE_OF_SPECIFIC_ANTIBODY_RESPONSE_TO_UNCONJUGATED_PNEUMOCOCCUS_VACCINE


collection_name: C2:CP:KEGG_MEDICUS
license_code: CC-BY-4.0
standard_name:
  KEGG_MEDICUS_REFERENCE_REGULATION_OF_TNF_NFKB_SIGNALING_PATHWAY_LUBAC_MEDIATED_LINEAR_UBIQUITINATION


collection_name: C2:CP:KEGG_MEDICUS
license_code: CC-BY-4.0
standard_name:
  KEGG_MEDICUS_VARIANT_MUTATION_CAUSED_ABERRANT_ABETA_TO_CROSSTALK_BETWEEN_EXTRINSIC_AND_INTRINSIC_APOPTOTIC_PATHWAYS


collection_name: C2:CP:KEGG_MEDICUS
license_code: CC-BY-4.0
standard_name:
  KEGG_MEDICUS_REFERENCE_AUTOPHAGY_VESICLE_NUCLEATION_ELONGATION_MATURATION_SEQUESTOSOME_1_LIKE_RECEPTOR


collection_name: C2:CP:KEGG_MEDICUS
license_code: CC-BY-4.0
standard_name:
  KEGG_MEDICUS_REFERENCE_AUTOPHAGY_VESICLE_NUCLEATION_ELONGATION_MATURATION_PI3P_SYNTHESIS_BY_PI3KC3_C1


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_TRANSCRIPTION_OF_E2F_TARGETS_UNDER_NEGATIVE_CONTROL_BY_P107_RBL1_AND_P130_RBL2_IN_COMPLEX_WITH_HDAC1


collection_name: C2:CP:REACTOME
license_code: CC-BY-4.0
standard_name:
  REACTOME_INHIBITION_OF_THE_PROTEOLYTIC_ACTIVITY_OF_APC_C_REQUIRED_FOR_THE_ONSET_OF_ANAPHASE_BY_MITOTIC_SPINDLE_CHECKPOINT_COMPONENTS


# gene_set_details

systematic_name: M1344
exact_source: Table S2
source_species_code: MM
GEO_id: GSE9651
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in tumorous  liver tissues from PARK2 [GeneID=5071] knockout mice compared to the normal, non-tumorous tissue from wild type mice.

description_full:
  The parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism. Deregulation of the parkin gene, however, has been observed in various human cancers, suggesting that the parkin gene may be important in tumorigenesis. To gain insight into the physiologic role of parkin, we generated parkin-/- mice lacking exon 3 of the parkin gene. We demonstrated here that parkin-/- mice had enhanced hepatocyte proliferation and developed macroscopic hepatic tumors with the characteristics of hepatocellular carcinoma. Microarray analyses revealed that parkin deficiency caused the alteration of gene expression profiles in the liver. Among them, endogenous follistatin is commonly upregulated in both nontumorous and tumorous liver tissues of parkin-deficient mice. Parkin deficiency resulted in suppression of caspase activation and rendered hepatocytes resistant to apoptosis in a follistatin-dependent manner. These results suggested that parkin deficiency caused enhanced hepatocyte proliferation and resistance to apoptosis, resulting in hepatic tumor development, partially through the upregulation of endogenous follistatin. The finding that parkin-deficient mice are susceptible to hepatocarcinogenesis provided the first evidence showing that parkin is indeed a tumor suppressor gene.


systematic_name: M778
exact_source: Figure 5A
source_species_code: MM
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Inflammatory genes down-regulated in mammary carcinoma cells after stimulation with TGFB1 [GeneID=7040] for 1 hr.

description_full:
  Transforming growth factor (TGF)-beta signaling has been associated with early tumor suppression and late tumor progression; however, many of the mechanisms that mediate these processes are not known. Using Cre/LoxP technology, with the whey acidic protein promoter driving transgenic expression of Cre recombinase (WAP-Cre), we have now ablated the type II TGF-beta receptor (T beta RII) expression specifically within mouse mammary alveolar progenitors. Transgenic expression of the polyoma virus middle T antigen, under control of the mouse mammary tumor virus enhancer/promoter, was used to produce mammary tumors in the absence or presence of Cre (T beta RII((fl/fl);PY) and T beta RII((fl/fl);PY;WC), respectively). The loss of TGF-beta signaling significantly decreased tumor latency and increased the rate of pulmonary metastasis. The loss of TGF-beta signaling was significantly correlated with increased tumor size and enhanced carcinoma cell survival. In addition, we observed significant differences in stromal fibrovascular abundance and composition accompanied by increased recruitment of F4/80(+) cell populations in T beta RII((fl/fl);PY;WC) mice when compared with T beta RII((fl/fl);PY) controls. The recruitment of F4/80(+) cells correlated with increased expression of known inflammatory genes including Cxcl1, Cxcl5, and Ptgs2 (cyclooxygenase-2). Notably, we also identified an enriched K5(+) dNp63(+) cell population in primary T beta RII((fl/fl);PY;WC) tumors and corresponding pulmonary metastases, suggesting that loss of TGF-beta signaling in this subset of carcinoma cells can contribute to metastasis. Together, our current results indicate that loss of TGF-beta signaling in mammary alveolar progenitors may affect tumor initiation, progression, and metastasis through regulation of both intrinsic cell signaling and adjacent stromal-epithelial interactions in vivo.


systematic_name: M48211
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes in breast cancer cells merged from 146 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. We derived the percentile of gene expression change for each individual gene normalized to all genes expression changes within each experiment, and filtered out genes that were detected in less than 80% of experiments. We derived consistency-to-inducibility maps consisting of 12,429 genes across 146 comparisons. We identified 65 upregulated and 22 downregulated genes that were enriched in top 10% percentile of altered genes and consistent across at least 50% of comparisons as the meta estrogene up and down regulation signatures.

exact_source:
  Supplementary Table S8: High condifent E2 regulated genes.  Detailed GEO IDs of all the datasets used can be found in Supplementary Table S1 Inventory of EstroGene Database of the publication.


systematic_name: M48212
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen down-regulated genes in breast cancer cells merged from 146 NGS datasets-based comparisons (10% topmost down-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. We derived the percentile of gene expression change for each individual gene normalized to all genes expression changes within each experiment, and filtered out genes that were detected in less than 80% of experiments. We derived consistency-to-inducibility maps consisting of 12,429 genes across 146 comparisons. We identified 65 upregulated and 22 downregulated genes that were enriched in top 10% percentile of altered genes and consistent across at least 50% of comparisons as the meta estrogene up and down regulation signatures.

exact_source:
  Supplementary Table S8: High condifent E2 regulated genes.  Detailed GEO IDs of all the datasets used can be found in Supplementary Table S1 Inventory of EstroGene Database of the publication.


systematic_name: M48213
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes in early treatment duration (&le;6 hours) in breast cancer cells merged from 58 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. Among the 146 merged transcriptomic datasets, 27 different time points were annotated spanning from 5 minutes to 600 hours of estrogen stimulation. We separated all the comparisons into three signatures of duration: EstroGene_Early (&le;6 hours, n = 58), EstroGene_Mid (6-24 hours, n = 44) and EstroGene_Late (&ge; 24 hours, n = 44). Upregulated and downregulated genes present in the top 10th percentile of regulated genes in each individual study, and consistently present across at least 50% of studies at each time period, were extracted from each signature (early, mid, and late) and intersected accordingly. We identified 165, 59 and 136 genes representing early, mid, and late estrogen response signatures, respectively.

exact_source:
  Supplementary Table S10: EstroGene temporal, contextual and directional signatures.  Detailed GEO IDs of all the datasets used can be found in Supplementary Table S1 Inventory of EstroGene Database of the publication.


systematic_name: M48214
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen down-regulated genes in early treatment duration (&le;6 hours) in breast cancer cells merged from 58 NGS datasets-based comparisons (10% topmost down-regulated genes and consistent in at least 40% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. Among the 146 merged transcriptomic datasets, 27 different time points were annotated spanning from 5 minutes to 600 hours of estrogen stimulation. We separated all the comparisons into three signatures of duration: EstroGene_Early (&le;6 hours, n = 58), EstroGene_Mid (6-24 hours, n = 44) and EstroGene_Late (&ge; 24 hours, n = 44). Upregulated and downregulated genes present in the top 10th percentile of regulated genes in each individual study, and consistently present across at least 50% of studies at each time period, were extracted from each signature (early, mid, and late) and intersected accordingly. We identified 165, 59 and 136 genes representing early, mid, and late estrogen response signatures, respectively.

exact_source:
  Supplementary Table S10: EstroGene temporal, contextual and directional signatures.  Detailed GEO IDs of all the datasets used can be found in Supplementary Table S1 Inventory of EstroGene Database of the publication.


systematic_name: M48215
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes in middle treatment duration (6-24 hours) in breast cancer cells merged from 44 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. Among the 146 merged transcriptomic datasets, 27 different time points were annotated spanning from 5 minutes to 600 hours of estrogen stimulation. We separated all the comparisons into three signatures of duration: EstroGene_Early (&le;6 hours, n = 58), EstroGene_Mid (6-24 hours, n = 44) and EstroGene_Late (&ge; 24 hours, n = 44). Upregulated and downregulated genes present in the top 10th percentile of regulated genes in each individual study, and consistently present across at least 50% of studies at each time period, were extracted from each signature (early, mid, and late) and intersected accordingly. We identified 165, 59 and 136 genes representing early, mid, and late estrogen response signatures, respectively.

exact_source:
  Supplementary Table S10: EstroGene temporal, contextual and directional signatures.  Detailed GEO IDs of all the datasets used can be found in Supplementary Table S1 Inventory of EstroGene Database of the publication.


systematic_name: M48216
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen down-regulated genes in middle treatment duration (6-24 hours) in breast cancer cells merged from 44 NGS datasets-based comparisons (10% topmost down-regulated genes and consistent in at least 40% comparisons).

description_full:
[cell repeats an earlier one in this file: 1326 characters]

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48217
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes in early treatment duration (&ge; 24 hours) in breast cancer cells merged from 44 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 50% comparisons).

description_full:
[cell repeats an earlier one in this file: 1326 characters]

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48218
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen down-regulated genes in early treatment duration (&ge; 24 hours) in breast cancer cells merged from 44 NGS datasets-based comparisons (10% topmost down-regulated genes and consistent in at least 40% comparisons).

description_full:
[cell repeats an earlier one in this file: 1326 characters]

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48219
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes exclusively in MCF7 cells merged from 74 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. MCF7 and T47D cell lines have been used extensively as ER+ breast cancer models. However, extrapolation of this data to breast cancer is complicated by the known heterogeneity of breast cancer and potential biases arising from cell line-specific results. Importantly, while EstroGene contains transcriptomic data from 19 different breast cancer cell lines, data from MCF7 and T47D account for ~50% and ~20%, respectively, of all experiments . To characterize and describe contextual cell-line specific responses, we identified the top 10th percentile of upregulated and downregulated genes in an individual study and consistent among 50% of comparisons within MCF7 or T47D experiments. For non-MCF7/T47D experiments we lowered the threshold to 40% across studies due to the larger heterogeneity in this subset. Intersection of the three subsets yielded 89 and 96 uniquely regulated genes in MCF7 and T47D, we also identified 26 genes that were not regulated in MCF7 and T47D but showed E2-induction in some other cell lines.

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48220
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen down-regulated genes exclusively in MCF7 cells merged from 74 NGS datasets-based comparisons (10% topmost down-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. MCF7 and T47D cell lines have been used extensively as ER+ breast cancer models. However, extrapolation of this data to breast cancer is complicated by the known heterogeneity of breast cancer and potential biases arising from cell line-specific results. Importantly, while EstroGene contains transcriptomic data from 19 different breast cancer cell lines, data from MCF7 and T47D account for ~50% and ~20%, respectively, of all experiments . To characterize and describe contextual cell-line specific responses, we identified the top 10th percentile of upregulated and downregulated genes in an individual study and consistent among 50% of comparisons within MCF7 or T47D experiments. For non-MCF7/T47D experiments we lowered the threshold to 40% across studies due to the larger heterogeneity in this subset. Intersection of the three subsets yielded 89 and 96 uniquely regulated genes in MCF7 and T47D, we also identified 26 genes that were not regulated in MCF7 and T47D but showed E2-induction in some other cell lines.

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48221
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes exclusively in T47D cells merged from 28 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 50% comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. MCF7 and T47D cell lines have been used extensively as ER+ breast cancer models. However, extrapolation of this data to breast cancer is complicated by the known heterogeneity of breast cancer and potential biases arising from cell line-specific results. Importantly, while EstroGene contains transcriptomic data from 19 different breast cancer cell lines, data from MCF7 and T47D account for ~50% and ~20%, respectively, of all experiments . To characterize and describe contextual cell-line specific responses, we identified the top 10th percentile of upregulated and downregulated genes in an individual study and consistent among 50% of comparisons within MCF7 or T47D experiments. For non-MCF7/T47D experiments we lowered the threshold to 40% across studies due to the larger heterogeneity in this subset. Intersection of the three subsets yielded 89 and 96 uniquely regulated genes in MCF7 and T47D, we also identified 26 genes that were not regulated in MCF7 and T47D but showed E2-induction in some other cell lines.

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48222
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen down-regulated genes exclusively in T47D cells merged from 28 NGS datasets-based comparisons (10% topmost down-regulated genes and consistent in at least 50% comparisons).

description_full:
[cell repeats an earlier one in this file: 1623 characters]

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48223
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  High confident estrogen up-regulated genes in non-MCF7/T47D breast cancer cell lines merged from 44 NGS datasets-based comparisons (10% topmost up-regulated genes and consistent in at least 40% comparisons).

description_full:
[cell repeats an earlier one in this file: 1623 characters]

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48225
external_details_URL: https://estrogene.org/
source_species_code: HS
contributor: Zheqi Li
contrib_organization: University of Pittsburgh
description_brief:
  Bidirectional estrogen regulated genes in breast cancer cell lines merged from 146 NGS datasets-based comparisons (present in the top 10% of both upregulated and downregulated targets in at least 10% of comparisons).

description_full:
  As one of the most successful cancer therapeutic targets, estrogen receptor-alpha (ER/ESR1) has been extensively studied over the past few decades. Sequencing technological advances have enabled genome-wide analysis of ER action. However, comparison of individual studies is limited by different experimental designs, and few meta-analyses are available. Here, by ingesting large amount of E2-related transcriptomic data sets in breast cancer cell lines, we identified gene expression changes across 66 RNA-seq and 80 microarray experiments based upon the E2-induced fold change in gene expression. By examining the plasticity of the directionality of estrogen response, we found the correlation of upregulation and downregulation of all 12,429 genes in the merged data collection revealed a strong nonlinear negative association, showing that most genes exhibited a single monodirectional regulation by estradiol. Unexpectedly, we also identified a subset of bidirectionally regulated genes (n = 101) that are present in the top 10% of both upregulated and downregulated targets and in at least 10% of comparisons. Their divergent regulation was not associated with specific experimental conditions such as E2 treatment duration or cell line context

exact_source:
[cell repeats an earlier one in this file: 217 characters]


systematic_name: M48226
exact_source: Supplementary Table 1: commonAll (column S)
source_species_code: HS
contributor: Timothy J Purwin
contrib_organization: Thomas Jefferson University
description_brief:
  Genes with a SOX10 ChIP-seq peak in the promoter region that are commonly down-regulated in two A375 and two MeWo CRISPR SOX10 knockout clones.

description_full:
  SOX10 is a transcription factor involved with neural crest development and is expressed in cutaneous melanoma. Loss of SOX10 in cutaneous melanoma has been linked to an invasive phenotype as well as resistance to MAPK targeted therapies. Transcriptomic changes due to SOX10 loss was modeled using RNA-seq data from CRISPR knockout in A375 and MeWo melanoma cell lines. SOX10 gene targets were prioritized using Ensembl Regulatory build promoter region data as well as SOX10 ChIP-seq peak call data from the GTRD for the melanoma cell line Mel501. Signature genes were generated from the intersect of ChIP-seq target genes and significantly (BHFDR < 0.05) down-regulated genes.

external_details_URL:
  https://www.cell.com/cms/10.1016/j.isci.2023.107472/attachment/44025f57-4dce-4fc4-8934-410f4e69c4c8/mmc2.xlsx


systematic_name: M48227
exact_source: Table S1: commonA375 (column M)
source_species_code: HS
contributor: Timothy J Purwin
contrib_organization: Thomas Jefferson University
description_brief:
  Genes with a SOX10 ChIP-seq peak in the promoter region that are commonly down-regulated (BHFDR < 0.05) in two A375 CRISPR SOX10 knockout clones.

description_full:
  SOX10 is a transcription factor involved with neural crest development and is expressed in cutaneous melanoma. Loss of SOX10 in cutaneous melanoma has been linked to an invasive phenotype as well as resistance to MAPK targeted therapies. Transcriptomic changes due to SOX10 loss was modeled using RNA-seq data from CRISPR knockout in A375 and MeWo melanoma cell lines. SOX10 gene targets were prioritized using Ensembl Regulatory build promoter region data as well as SOX10 ChIP-seq peak call data from the GTRD for the melanoma cell line Mel501. Signature genes were generated from the intersect of ChIP-seq target genes and significantly (BHFDR < 0.05) down-regulated genes.

external_details_URL:
  https://www.cell.com/cms/10.1016/j.isci.2023.107472/attachment/44025f57-4dce-4fc4-8934-410f4e69c4c8/mmc2.xlsx


systematic_name: M48228
exact_source: Supplementary Table 1: commonMewo (column P)
source_species_code: HS
contributor: Timothy J Purwin
contrib_organization: Thomas Jefferson University
description_brief:
  Genes with a SOX10 ChIP-seq peak in the promoter region that are commonly down-regulated (BHFDR < 0.05) in two MeWo CRISPR SOX10 knockout clones.

description_full:
  SOX10 is a transcription factor involved with neural crest development and is expressed in cutaneous melanoma. Loss of SOX10 in cutaneous melanoma has been linked to an invasive phenotype as well as resistance to MAPK targeted therapies. Transcriptomic changes due to SOX10 loss was modeled using RNA-seq data from CRISPR knockout in A375 and MeWo melanoma cell lines. SOX10 gene targets were prioritized using Ensembl Regulatory build promoter region data as well as SOX10 ChIP-seq peak call data from the GTRD for the melanoma cell line Mel501. Signature genes were generated from the intersect of ChIP-seq target genes and significantly (BHFDR < 0.05) down-regulated genes.

external_details_URL:
  https://www.cell.com/cms/10.1016/j.isci.2023.107472/attachment/44025f57-4dce-4fc4-8934-410f4e69c4c8/mmc2.xlsx


systematic_name: M216
exact_source: Fig. 2A
source_species_code: HS
GEO_id: GSE5675
contributor: Jessica Robertson
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pilocytic astrocytoma (PA) samples from patients with type 1 neurofibromatosis syndrom (NF1) compared to the PA tumors from non-NF1 patients.

description_full:
  Pilocytic astrocytomas (PAs) are the most common glioma in children. Whereas many PAs are slow-growing or clinically indolent, others exhibit more aggressive features with tumor recurrence and death. To identify genetic signatures that might predict PA clinical behavior, we did gene expression profiling on 41 primary PAs arising sporadically and in patients with neurofibromatosis type 1 (NF1). Whereas no expression signature was found that could discriminate clinically aggressive or recurrent tumors from more indolent cases, PAs arising in patients with NF1 did exhibit a unique gene expression pattern. In addition, we identified a gene expression signature that stratified PAs by location (supratentorial versus infratentorial). Lastly, we also identified a gene expression pattern common to PAs and normal mouse astrocytes and neural stem cells from these distinct brain regions as well as a gene expression pattern shared between PAs and another human glial tumor (ependymoma) arising supratentorially compared with those originating in the posterior fossa. These results suggest that glial tumors share an intrinsic, lineage-specific molecular signature that reflects the brain region in which their nonmalignant predecessors originated.


description_brief: Metabolic related genes that showed negative correlation with MYC expression in CRC tissues
systematic_name: M45006
exact_source: Table S3: Candidate MYC target metabolic genes
source_species_code: HS
GEO_id: GSE89076
contributor: Rintaro Saito
contrib_organization: Institute for Advanced Biosciences, Keio University
description_full:
  Our transcriptome analyses of paired normal and tumor tissues from 41 patients with colorectal cancer showed that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression, which induced at least 215 metabolic reactions by changing the expression levels of metabolic genes and transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth.

external_details_URL:
  https://www.pnas.org/content/pnas/suppl/2017/08/25/1710366114.DCSupplemental/pnas.1710366114.sapp.pdf


description_brief: Direct target genes of the transcription factor and emerging tumor suppressor RFX7.
systematic_name: M42500
exact_source: Table 1
source_species_code: HS
GEO_id: GSE162184
contributor: Martin Fischer
contrib_organization: Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)
description_full:
  RFX7 is an emerging tumor suppressor that is activated in response to p53 and stress. Integrative analysis of the RFX7 DNA binding landscape (ChIP-seq) and the RFX7-regulated transcriptome (RNA-seq) in three distinct cell systems revealed direct RFX7 target genes. Direct RFX7 target genes identified in at least two of the three cell lines comprise a set of 57 genes.


systematic_name: M42501
exact_source: Table S1. TGF_-EMT signature, https://doi.org/10.4225/49/5a2a11fa43fe3
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_brief:
  Genes up-regulated in the epithelial-mesenchymal transition (EMT) upon transforming growth factor beta (TGFb) stimulation derived from multiple datasets by combining results from an integrative approach and a product of ranks meta-analysis approach.

description_full:
  Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGF_ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGF_-induced EMT which can be used to score TGF_-driven EMT in cells and clinical specimens. Multiple datasets were used to derive the signature using three approaches: by integrating the datasets prior to identifying EMT genes, by first identifying EMT genes from individual datasets and then combining them using a meta-analysis (product of ranks) approach, and by combining inferences from the first two approaches.

external_details_URL:
  https://mcr.aacrjournals.org/highwire/filestream/36853/field_highwire_adjunct_files/2/171996_1_supp_3789008_cccpcz.docx


systematic_name: M42502
exact_source: Table S1. TGF_-EMT signature, https://doi.org/10.4225/49/5a2a11fa43fe3
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_brief:
  Genes down-regulated in the epithelial-mesenchymal transition (EMT) upon transforming growth factor beta (TGFb) stimulation derived from multiple datasets by combining results from an integrative approach and a product of ranks meta-analysis approach.

description_full:
  Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGF_ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGF_-induced EMT which can be used to score TGF_-driven EMT in cells and clinical specimens. Multiple datasets were used to derive the signature using three approaches: by integrating the datasets prior to identifying EMT genes, by first identifying EMT genes from individual datasets and then combining them using a meta-analysis (product of ranks) approach, and by combining inferences from the first two approaches.

external_details_URL:
  https://mcr.aacrjournals.org/highwire/filestream/36853/field_highwire_adjunct_files/2/171996_1_supp_3789008_cccpcz.docx


systematic_name: M42503
exact_source: Table S1. TGF_-EMT signature, https://doi.org/10.4225/49/5a2a11fa43fe3
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_brief:
  Genes up-regulated in the epithelial-mesenchymal transition (EMT) upon transforming growth factor beta (TGFb) stimulation derived from multiple datasets using a product of ranks meta-analysis approach.

description_full:
  Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGF_ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGF_-induced EMT which can be used to score TGF_-driven EMT in cells and clinical specimens. Multiple datasets were used to derive the signature using three approaches: by integrating the datasets prior to identifying EMT genes, by first identifying EMT genes from individual datasets and then combining them using a meta-analysis (product of ranks) approach, and by combining inferences from the first two approaches.

external_details_URL:
  https://mcr.aacrjournals.org/highwire/filestream/36853/field_highwire_adjunct_files/2/171996_1_supp_3789008_cccpcz.docx


systematic_name: M42504
exact_source: Table S1. TGF_-EMT signature, https://doi.org/10.4225/49/5a2a11fa43fe3
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_brief:
  Genes down-regulated in the epithelial-mesenchymal transition (EMT) upon transforming growth factor beta (TGFb) stimulation derived from multiple datasets using a product of ranks meta-analysis approach.

description_full:
[cell repeats an earlier one in this file: 857 characters]

external_details_URL:
[cell repeats an earlier one in this file: 119 characters]


systematic_name: M42505
exact_source: Table S1. TGF_-EMT signature, https://doi.org/10.4225/49/5a2a11fa43fe3
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_brief:
  Genes up-regulated in the epithelial-mesenchymal transition (EMT) upon transforming growth factor beta (TGFb) stimulation derived from multiple datasets by integrating them.

description_full:
[cell repeats an earlier one in this file: 857 characters]

external_details_URL:
[cell repeats an earlier one in this file: 119 characters]


systematic_name: M42506
exact_source: Table S1. TGF_-EMT signature, https://doi.org/10.4225/49/5a2a11fa43fe3
source_species_code: HS
contributor: Dharmesh D. Bhuva
contrib_organization: Walter and Eliza Hall Institute of Medical Research
description_brief:
  Genes down-regulated in the epithelial-mesenchymal transition (EMT) upon transforming growth factor beta (TGFb) stimulation derived from multiple datasets by integrating them.

description_full:
[cell repeats an earlier one in this file: 857 characters]

external_details_URL:
[cell repeats an earlier one in this file: 119 characters]


systematic_name: M42507
exact_source: Table 3S: DPPs, samples_with_CLIP_sites > 0
source_species_code: HS
GEO_id: GSE161101
contributor: Markus Gla&szlig;
contrib_organization: Martin Luther University Halle-Wittenberg
description_brief:
  Transcripts bound to IGF2BP1 and consistently downregulated upon IGF2BP1 knockdown in various cancer derived cell lines.

description_full:
  The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) promotes tumor progression in a variety of solid tumors and its expression is associated with adverse prognosis. The main role proposed for IGF2BP1 in cancer cells is the stabilization of mRNAs encoding pro-oncogenic factors. This set contains 117 genes, consistently downregulated upon the knockdown of IGF2BP1 in various cancer derived cell lines. Furthermore, these 117 genes showed a positive correlation in RNA expression with IGF2BP1 in the majority of TCGA tumor cohorts and their transcripts were identified as direct IGF2BP1 targets by CLIP-seq experiments.


systematic_name: M42508
exact_source: https://housekeeping.unicamp.br/Human_Mouse_Common.csv
external_details_URL: https://housekeeping.unicamp.br/?about
source_species_code: HS
contributor: Bidossessi Wilfried Hounkpe
contrib_organization: Unicamp
description_brief:
  List of 1130 human and mouse housekeeping genes. This list shows the overlap of human genes stably expressed across 52 tissues and cells types and mouse genes with at least one of their transcripts expressed across 14 tissues and cells types.

description_full:
  Housekeeping (HK) genes are constitutively expressed genes that are required for the maintenance of basic cellular functions. Despite their importance in the calibration of gene expression, as well as the understanding of many genomic and evolutionary features, important discrepancies have been observed in studies that previously identified these genes. Here, we present Housekeeping and Reference Transcript Atlas (HRT Atlas v1.0, www.housekeeping.unicamp.br) a web-based database which addresses some of the previously observed limitations in the identification of these genes and offers a more accurate database of human HK genes and transcripts. The database was generated by mining massive human and mouse RNA-seq data sets, including 11 281 and 507 high-quality RNA-seq samples from 52 human non-disease tissues/cells and 14 healthy tissues/cells of C57BL/6 wild type mouse, respectively. Overall, 2176 housekeeping genes have been identified in this study.


description_brief: Genes up-regulated in HEK293T cells overexpressing FLAG-NRF1
systematic_name: M42509
exact_source: Table 6S: MSigDB Genesets
external_details_URL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159230
source_species_code: HS
GEO_id: GSE159230
contributor: Lara Ibrahim
contrib_organization: The Scripps Research Institute
description_full:
  The NRF transcription factors NRF1, NRF2, and NRF3, are a subset of Cap'n'collar transcriptional regulators which modulate the expression of genes harboring antioxidant-response element (ARE) sequences within their genomic loci. Despite the emerging physiological importance of NRF family members, the repertoire of their genetic targets remains incompletely defined. Here we use RNA-sequencing-based transcriptional profiling and quantitative proteomics to delineate the overlapping and differential genetic programs effected by the three NRF transcription factors. Comparing our data to recent profiling analyses, we create consensus target gene sets regulated by NRF1, NRF2, and NRF3, genetic programs which we determine to be differentially regulated in human tissues. Together, our data provide a quantitative assessment of how NRF family members sculpt proteomes and transcriptomes, essential information for future studies evaluating the role of NRF factors in normal physiology and disease.


description_full: Epithelioid Hemangioendothelioma (EHE) is a
systematic_name: M42516
exact_source: Figure 3D
external_details_URL: http://genesdev.cshlp.org/content/early/2021/03/22/gad.348220.120
source_species_code: HS
GEO_id: GSE168493
contributor: Caleb Seavey
contrib_organization: Cleveland Clinic Foundation
description_brief:
  Genes overexpressed in Epithelioid Hemangioendothelioma versus Angiosarcoma, Kaposi Sarcoma, Hemangioblastoma, and Liver


systematic_name: M40000
exact_source: noab001_suppl_Supplementary_Table_S3 PIRLE, CORE ENRICHMENT = YES
external_details_URL: https://doi.org/10.1093/neuonc/noab001
source_species_code: HS
GEO_id: GSE163906
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  102 proteins were identified that were specifically and significantly accumulated after proteasome inhibition with carfilzomibin the PTEN-KO GBM spheres compared with placebo-treated and were not statistically present in the PTEN-WT drug vs placebo group at the proteomic level, this proteomic signature was then coorelated with the RNA-level transcriptomic response to carfilzomib using GSEA. The leading edge of the enrichment result was selected as the response signature.

description_full:
  Background <BR/>Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months, therefore, more effective treatment options for GBM are required. To identify new drugs targeting glioblastomas, we performed a high throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype. <BR/>Results<BR/>We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome, resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in3D glioblastoma organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition.<BR/>Conclusions<BR/>Proteasome inhibition is a potential synthetic lethal therapeutic strategy for GBM with proteasome addiction due to a high protein synthesis rate and autophagy deficiency


description_brief: Genes up-regulated in SARS-CoV-1 infection (MRC5 cells, MOI: 3, 24hpi).
systematic_name: M34000
source_species_code: HS
GEO_id: GSE56192
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
  Analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses, including MERS-CoV, SARS-CoV-1 (SARS), human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and IAV.

exact_source:
  Table S1. Differential Gene Expression Analysis of Respiratory Virus Infections in Cell Lines, Related to Figure 1. log2(FC)>1, padj<0.05


description_brief: Genes down-regulated in SARS-CoV-1 infection (MRC5 cells, MOI: 3, 24hpi).
systematic_name: M34001
source_species_code: HS
GEO_id: GSE56192
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
  Analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses, including MERS-CoV, SARS-CoV-1 (SARS), human parainfluenza virus 3 (HPIV3), respiratory syncytial virus (RSV), and IAV.

exact_source:
  Table S1. Differential Gene Expression Analysis of Respiratory Virus Infections in Cell Lines, Related to Figure 1. log2(FC)<-1, padj<0.05


description_brief: Genes up-regulated in HPIV3 (A549 cells, MOI: 2, 24hpi)
systematic_name: M34006
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S1. Differential Gene Expression Analysis of Respiratory Virus Infections in Cell Lines, Related to Figure 1. log2(FC)>1.58, padj<0.05


description_brief: Genes down-regulated in HPIV3 (A549 cells, MOI: 2, 24hpi)
systematic_name: M34007
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S1. Differential Gene Expression Analysis of Respiratory Virus Infections in Cell Lines, Related to Figure 1. log2(FC)<-1.58, padj<0.05


description_brief: Genes up-regulated in RSV (A549 cells, MOI: 2, 24hpi)
systematic_name: M34008
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S1. Differential Gene Expression Analysis of Respiratory Virus Infections in Cell Lines, Related to Figure 1. log2(FC)>2, padj<0.05


description_brief: Genes down-regulated in RSV (A549 cells, MOI: 2, 24hpi)
systematic_name: M34009
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S1. Differential Gene Expression Analysis of Respiratory Virus Infections in Cell Lines, Related to Figure 1. log2(FC)<-2, padj<0.05


systematic_name: M34018
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in SARS-CoV-2 infection with Ruxolitinib (ACE2 expressing A549 cells, MOI: 2, 24hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
[cell repeats an earlier one in this file: 137 characters]


systematic_name: M34019
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SARS-CoV-2 infection with Ruxolitinib (ACE2 expressing A549 cells, MOI: 2, 24hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
[cell repeats an earlier one in this file: 138 characters]


systematic_name: M34020
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated on infection of normal human bronchial epithelial cells by SARS-CoV-2 (MOI: 2, 24hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)>0.58, padj<0.05


systematic_name: M34021
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)<-0.58, padj<0.05


systematic_name: M34022
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated on treatment of normal human bronchial epithelial cells with beta interferon (hIFNB treatment 100u/ml, 4-12hrs).

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)>1, padj<0.05


systematic_name: M34023
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated on treatment of normal human bronchial epithelial cells with beta interferon (hIFNB treatment 100u/ml, 4-12hrs).

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)<-1, padj<0.05


systematic_name: M34024
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated oninfection of normal human bronchial epithelial cells by Influenza A (MOI: 3, 12hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)>1, padj<0.05


systematic_name: M34025
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated oninfection of normal human bronchial epithelial cells by Influenza A (MOI: 3, 12hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)<-1, padj<0.05


systematic_name: M34026
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated on infection of normal human bronchial epithelial cells by mutant Influenza A lacking its antiviral antagonist (IAV_NS1) (MOI: 3, 12hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)>1, padj<0.05


systematic_name: M34027
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated on infection of normal human bronchial epithelial cells by mutant Influenza A lacking its antiviral antagonist (IAV_NS1) (MOI: 3, 12hpi)

description_full:
[cell repeats an earlier one in this file: 215 characters]

exact_source:
  Table S2. Differential Gene Expression Analysis of Experiments Performed in NHBE Cells, Related to Figure 2. log2(FC)<-1, padj<0.05


systematic_name: M34028
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes strongly up-regulated (log2(FC)>3.58, padj<0.05) in post mortem lung tissue from COVID-19 patients vs uninfected biopsy.

description_full:
  Transcriptional profiling of post-mortem lung samples from COVID-19-positive patients compared with biopsied healthy lung tissue from uninfected individuals.

exact_source:
  Table S4. Differential Gene Expression Analysis of COVID-19 Patients, Related to Figure 4. log2(FC)>3.58, padj<0.05


systematic_name: M34029
source_species_code: HS
GEO_id: GSE147507
contributor: Anthony Castanza
contrib_organization: MSigDB Team
description_brief:
  Genes strongly down-regulated (og2(FC)<-3.58, padj<0.05) in post mortem lung tissue from COVID-19 patients vs uninfected biopsy.

description_full:
  Transcriptional profiling of post-mortem lung samples from COVID-19-positive patients (N=2) compared with biopsied healthy lung tissue from uninfected individuals.

exact_source:
  Table S4. Differential Gene Expression Analysis of COVID-19 Patients, Related to Figure 4. log2(FC)<-3.58, padj<0.05


systematic_name: M34030
source_species_code: HS
contributor: Francesca Buffa
contrib_organization: University of Oxford
description_brief:
  Common genes regulated by hypoxia across multiple head and neck and breast cancer clinical cohorts, and prognostic in multiple cancer types

description_full:
  Hypoxia is a key factor promoting solid tumour progression and resistance to therapy. Hypoxia biomarkers have the potential to predict prognosis and/or benefit from particular interventions. An approach combining knowledge of gene function and analysis of in vivo co-expression patterns was used to derive a gene expression signature of hypoxia. Specifically, previously validated hypoxia-regulated genes (seeds) were used to generate a co-expression network. To guarantee generality and robustness of this network, bootstrap was used to select genes that were consistently co-expressed with the hypoxia seeds in multiple cancers cohorts and across cancer types (three head and neck and five breast cancer clinical cohorts were used in this phase). Genes with the highest connectivity in the resulting co-expression gene network were extracted to form a hypoxia gene signature. This signature was highly enriched for hypoxia-regulated pathways, enriched for targets of the Hypoxia-Inducible Factor (HIF)-1 as determined in ChipSeq and HIF know-down experiments, and prognostic. Validation in independent data sets of head and neck, breast and lung cancer showed that this signature outperformed previously reported hypoxia gene signatures.

exact_source:
  Table S5. Common Hypoxia Signature Genes ranked by the Common Connectvity Score (from highest to lowest) and their expression changes in cell lines experiments  of hypoxia exposure and HIF1a siRNA


description_brief: Top down-regulated genes in pediatric adrenocortical tumors (ACT) compared to the normal tissue.
systematic_name: M8321
exact_source: Table 2: Decreased
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Pediatric adrenocortical tumors (ACT) are rare and often fatal malignancies; little is known regarding their etiology and biology. To provide additional insight into the nature of ACT, we determined the gene expression profiles of 24 pediatric tumors (five adenomas, 18 carcinomas, and one undetermined) and seven normal adrenal glands. Distinct patterns of gene expression, validated by quantitative real-time PCR and Western blot analysis, were identified that distinguish normal adrenal cortex from tumor. Differences in gene expression were also identified between adrenocortical adenomas and carcinomas. In addition, pediatric adrenocortical carcinomas were found to share similar patterns of gene expression when compared with those published for adult ACT. This study represents the first microarray analysis of childhood ACT. Our findings lay the groundwork for establishing gene expression profiles that may aid in the diagnosis and prognosis of pediatric ACT, and in the identification of signaling pathways that contribute to this disease.


description_brief: Genes down-regulated in head and neck tumor samples which clustered around known hypoxia genes.
systematic_name: M2683
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.


systematic_name: M16644
exact_source: Table 2S
source_species_code: HS
GEO_id: E-MEXP-958
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HepaRG cells (liver cancer) expressing constituvely active form of MTOR [GeneID=2475].

description_full:
  The mammalian target of rapamycin (mTOR) pathway, a major regulator of translation, is frequently activated in hepatocellular carcinomas. We investigated the effects of mTOR activation in the human HepaRG cells, which possess potent hepatocytic differentiation capability. Differentiation of HepaRG cells into functional and polarized hepatocyte-like cells correlated with a decrease in mTOR and Akt activities. Stable cell lines expressing an activated mutant of mTOR were generated. Sustained activation of mTOR impaired the hepatocytic differentiation capability of these cells as shown by impaired formation of bile canaliculi, absence of polarity, and reduced secretion of alpha1-antitrypsin. An inhibitor of mTOR, rapamycin, was able to revert this phenotype. Furthermore, increased mTOR activity in HepaRG cells resulted in their resistance to the antiproliferative effects of transforming growth factor-beta1. Profiling of polysome-bound transcripts indicated that activated mTOR specifically targeted genes posttranscriptionally regulated on hepatocytic differentiation. Three major biological networks targeted by activated mTOR were identified: (a) cell death associated with tumor necrosis factor superfamily members, IFNs and caspases; (b) lipid homeostasis associated with the transcription factors PPARalpha, PPARdelta, and retinoid X receptor beta; and (c) liver development associated with CCAAT/enhancer binding protein alpha and hepatic mitogens. In conclusion, increased mTOR activity conferred a preneoplastic phenotype to the HepaRG cells by altering the translation of genes vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth.


systematic_name: M18367
exact_source: Table 3: t statistic < 0
source_species_code: HS
GEO_id: GSE6791
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in cervical carcinoma and head and neck tumors positive for human papilloma virus (HPV) compared to those negative for HPV.

description_full:
  Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV(+) HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV(-) HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV(+) HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV(-) HNC. Moreover, HPV(+) cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV(+) HNC and HPV(-) HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV(+) and HPV(-) cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV(+) cancers.


description_brief: Genes down-regulated in endothelial cells derived from invasive ovarian cancer tissue.
systematic_name: M14262
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Therapeutic strategies based on antiangiogenic approaches are beginning to show great promise in clinical studies. However, full realization of these approaches requires identification of key differences in gene expression between endothelial cells from tumors versus their normal counterparts. Here, we examined gene expression differences in purified endothelial cells from 10 invasive epithelial ovarian cancers and 5 normal ovaries using Affymetrix U133 Plus 2.0 microarrays. More than 400 differentially expressed genes were identified in tumor-associated endothelial cells. We selected and validated 23 genes that were overexpressed by 3.6- to 168-fold using real-time reverse transcription-PCR and/or immunohistochemistry. Among these, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), the Notch ligand Jagged1, and PTK2 were elevated 3- to 4.3-fold in tumor-associated endothelial cells. Silencing these genes individually with small interfering RNA blocked endothelial cell migration and tube formation in vitro. The present study shows that tumor and normal endothelium differ at the molecular level, which may have significant implications for the development of antiangiogenic therapies.


systematic_name: M12730
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE3218
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the 12p region that were up-regulated in embryonic carcinoma tumors compared to normal testis.

description_full:
  Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray ( approximately 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core stemness genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas.


systematic_name: M12977
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE3218
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the 12p region that were down-regulated in embryonic carcinoma tumors compared to normal tissue.

description_full:
  Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray ( approximately 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core stemness genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas.


systematic_name: M14050
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE3218
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the 12p region that were up-regulated in choriocarcinoma cells compared to normal testis.

description_full:
[cell repeats an earlier one in this file: 1746 characters]


systematic_name: M11068
exact_source: Table 3S
source_species_code: HS
GEO_id: GSE3218
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the 12p region that were down-regulated in choriocarcinoma cells compared to normal testis.

description_full:
[cell repeats an earlier one in this file: 1746 characters]


systematic_name: M1260
exact_source: Table 1S: non-responders / responders > 1
source_species_code: HS
GEO_id: GSE3493
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in rectal cancer patients resistant to radiotherapy (non-responders) relative to the sensitive ones (responders).

description_full:
  Preoperative radiotherapy has been widely used to improve local control of disease and to improve survival in the treatment of rectal cancer. However, the response to radiotherapy differs among individual tumors. Our objective here was to identify a set of discriminating genes that can be used for characterization and prediction of response to radiotherapy in rectal cancer. Fifty-two rectal cancer patients who underwent preoperative radiotherapy were studied. Biopsy specimens were obtained from rectal cancer before preoperative radiotherapy. Response to radiotherapy was determined by histopathologic examination of surgically resected specimens and classified as responders or nonresponders. By determining gene expression profiles using human U95Av2 Gene Chip, we identified 33 novel discriminating genes of which the expression differed significantly between responders and nonresponders. Using this gene set, we were able to establish a new model to predict response to radiotherapy in rectal cancer with an accuracy of 82.4%. The list of discriminating genes included growth factor, apoptosis, cell proliferation, signal transduction, or cell adhesion-related genes. Among 33 discriminating genes, apoptosis inducers (lumican, thrombospondin 2, and galectin-1) showed higher expression in responders whereas apoptosis inhibitors (cyclophilin 40 and glutathione peroxidase) showed higher expression in nonresponders. The present study suggested the possibility that gene expression profiling may be useful in predicting response to radiotherapy to establish an individualized tailored therapy for rectal cancer. Global expression profiles of responders and nonresponders may provide insights into the development of novel therapeutic targets.


systematic_name: M9695
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in DLBCL (diffuse large B-cell lymphoma) cell lines sensitive to stimulation of CD40 [GeneID=958] relative to the resistant ones.

description_full:
  CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.


description_brief: Genes up-regulated in prostate cancer samples.
systematic_name: M4619
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Prostate cancer is the most commonly diagnosed noncutaneous neoplasm and second most common cause of cancer-related mortality in western men. To investigate the mechanisms of prostate cancer development and progression, we did expression profiling of human prostate cancer and benign tissues. We show that the SOX4 is overexpressed in prostate tumor samples compared with benign tissues by microarray analysis, real-time PCR, and immunohistochemistry. We also show that SOX4 expression is highly correlated with Gleason score at the mRNA and protein level using tissue microarrays. Genes affected by SOX4 expression were also identified, including BCL10, CSF1, and NcoA4/ARA70. TLE-1 and BBC3/PUMA were identified as direct targets of SOX4. Silencing of SOX4 by small interfering RNA transfection induced apoptosis of prostate cancer cells, suggesting that SOX4 could be a therapeutic target for prostate cancer. Stable transfection of SOX4 into nontransformed prostate cells enabled colony formation in soft agar, suggesting that, in the proper cellular context, SOX4 can be a transforming oncogene.


systematic_name: M17450
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in LNCaP cells (prostate cancer) by overexpression of SOX4 [GeneID=6659] and down-regulated by its RNAi knockdown.

description_full:
  Prostate cancer is the most commonly diagnosed noncutaneous neoplasm and second most common cause of cancer-related mortality in western men. To investigate the mechanisms of prostate cancer development and progression, we did expression profiling of human prostate cancer and benign tissues. We show that the SOX4 is overexpressed in prostate tumor samples compared with benign tissues by microarray analysis, real-time PCR, and immunohistochemistry. We also show that SOX4 expression is highly correlated with Gleason score at the mRNA and protein level using tissue microarrays. Genes affected by SOX4 expression were also identified, including BCL10, CSF1, and NcoA4/ARA70. TLE-1 and BBC3/PUMA were identified as direct targets of SOX4. Silencing of SOX4 by small interfering RNA transfection induced apoptosis of prostate cancer cells, suggesting that SOX4 could be a therapeutic target for prostate cancer. Stable transfection of SOX4 into nontransformed prostate cells enabled colony formation in soft agar, suggesting that, in the proper cellular context, SOX4 can be a transforming oncogene.


description_brief: Genes up-regulated in medullary breast cancer (MBC) relative to ductal breast cancer (DBD).
systematic_name: M14539
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Medullary breast cancer (MBC) is a rare but enigmatic pathologic type of breast cancer. Despite features of aggressiveness, MBC is associated with a favorable prognosis. Morphologic diagnosis remains difficult in many cases. Very little is known about the molecular alterations involved in MBC. Notably, it is not clear whether MBC and ductal breast cancer (DBC) represent molecularly distinct entities and what genes/proteins might account for their differences. Using whole-genome oligonucleotide microarrays, we compared gene expression profiles of 22 MBCs and 44 grade III DBCs. We show that MBCs are less heterogeneous than DBCs. Whereas different molecular subtypes (luminal A, luminal B, basal, ERBB2-overexpressing, and normal-like) exist in DBCs, 95% MBCs display a basal profile, similar to that of basal DBCs. Supervised analysis identified gene expression signatures that discriminated MBCs from DBCs. Discriminator genes are associated with various cellular processes related to MBC features, in particular immune reaction and apoptosis. As compared with MBCs, basal DBCs overexpress genes involved in smooth muscle cell differentiation, suggesting that MBCs are a distinct subgroup of basal breast cancer with limited myoepithelial differentiation. Finally, MBCs overexpress a series of genes located on the 12p13 and 6p21 chromosomal regions known to contain pluripotency genes. Our results contribute to a better understanding of MBC and of mammary oncogenesis in general.


systematic_name: M4991
exact_source: Table 1: PAX-FKHR regulation = Up
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  'PAX-FKHR signature':  genes up-regulated by PAX3- or PAX7-FOXO1 [GeneID=5081;5077;2308] fusion in primary alveolar rhabdomyosarcoma(ARMS) tumors.

description_full:
  Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.


systematic_name: M3642
exact_source: Table 1: PAX-FKHR regulation = Down
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  'PAX-FKHR signature':  genes down-regulated by PAX3- or PAX7-FOXO1 [GeneID=5081;5077;2308] fusion in primary alveolar rhabdomyosarcoma(ARMS) tumors.

description_full:
  Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.


description_brief: Genes up-regulated early in HMEC cells (mammary epithelium) during acinar development in vitro.
systematic_name: M18424
exact_source: Table 1S: ue
source_species_code: HS
GEO_id: GSE8096
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Nonmalignant human mammary epithelial cells (HMEC) seeded in laminin-rich extracellular matrix (lrECM) form polarized acini and, in doing so, transit from a disorganized proliferating state to an organized growth-arrested state. We hypothesized that the gene expression pattern of organized and growth-arrested HMECs would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in 184 (finite life span) and HMT3522 S1 (immortal nonmalignant) HMECs on successive days after seeding in a lrECM assay. Both HMECs underwent growth arrest in G0-G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines and examined the expression of these genes in a previously published panel of microarray data for 295 breast cancer samples. We show that genes that are significantly lower in the organized, growth-arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of use clinically.


systematic_name: M7076
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MDA-MB-231 cells (breast cancer) after knockdown of FXYD5 [GeneID=53827] by RNAi.

description_full:
  Dysadherin, a cancer-associated membrane glycoprotein, down-regulates E-cadherin and promotes cancer metastasis. This study examined the role of dysadherin in breast cancer progression. Expression of dysadherin was found to be highest in breast cancer cell lines and tumors that lacked the estrogen receptor (ER). Knockdown of dysadherin caused increased association of E-cadherin with the actin cytoskeleton in breast cancer cell lines that expressed E-cadherin. However, knockdown of dysadherin could still suppress cell invasiveness in cells that had no functional E-cadherin, suggesting the existence of a novel mechanism of action. Global gene expression analysis identified chemokine (C-C motif) ligand 2 (CCL2) as the transcript most affected by dysadherin knockdown in MDA-MB-231 cells, and dysadherin was shown to regulate CCL2 expression in part through activation of the nuclear factor-kappaB pathway. The ability of dysadherin to promote tumor cell invasion in vitro was dependent on the establishment of a CCL2 autocrine loop, and CCL2 secreted by dysadherin-positive tumor cells also promoted endothelial cell migration in a paracrine fashion. Finally, experimental suppression of CCL2 in MDA-MB-231 cells reduced their ability to metastasize in vivo. This study shows that dysadherin has prometastatic effects that are independent of E-cadherin expression and that CCL2 could play an important role in mediating the prometastatic effect of dysadherin in ER-negative breast cancer.


systematic_name: M17651
exact_source: Table 1AS
source_species_code: HS
GEO_id: GSE4025
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes preferentially up-regulated in MCF-7 cells (breast cancer) by tamoxifen [PubChem=5376] but not by estradiol or fulvestrant (ICI 182780) [PubChem=5757;3478439].

description_full:
  The beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERalpha-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERalpha and reversed by E2 or ICI 182,780. Introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifen-stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy.


systematic_name: M5082
exact_source: Table 1BS
source_species_code: HS
GEO_id: GSE4025
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes preferentially down-regulated in MCF-7 cells (breast cancer) by tamoxifen [PubChem=5376] but not by estradiol or fulvestrant (ICI 182780) [PubChem=5757;3478439].

description_full:
  The beneficial effect of the selective estrogen receptor (ER) modulator tamoxifen in the treatment and prevention of breast cancer is assumed to be through its ability to antagonize the stimulatory actions of estrogen, although tamoxifen can also have some estrogen-like agonist effects. Here, we report that, in addition to these mixed agonist/antagonist actions, tamoxifen can also selectively regulate a unique set of >60 genes, which are minimally regulated by estradiol (E2) or raloxifene in ERalpha-positive MCF-7 human breast cancer cells. This gene regulation by tamoxifen is mediated by ERalpha and reversed by E2 or ICI 182,780. Introduction of ERbeta into MCF-7 cells reverses tamoxifen action on approximately 75% of these genes. To examine whether these genes might serve as markers of tamoxifen sensitivity and/or the development of resistance, their expression level was examined in breast cancers of women who had received adjuvant therapy with tamoxifen. High expression of two of the tamoxifen-stimulated genes, YWHAZ/14-3-3z and LOC441453, was found to correlate significantly with disease recurrence following tamoxifen treatment in women with ER-positive cancers and hence seem to be markers of a poor prognosis. Our data indicate a new dimension in tamoxifen action, involving gene expression regulation that is tamoxifen preferential, and identify genes that might serve as markers of tumor responsiveness or resistance to tamoxifen therapy. This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy.


systematic_name: M14954
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in glioma cell lines treated with both decitabine [PubChem=451668] and TSA [PubChem=5562].

description_full:
  Malignant glioma is the most common central nervous system tumor of adults and is associated with a significant degree of morbidity and mortality. Gliomas are highly invasive and respond poorly to conventional treatments. Gliomas, like other tumor types, arise from a complex and poorly understood sequence of genetic and epigenetic alterations. Epigenetic alterations leading to gene silencing, in the form of aberrant CpG island promoter hypermethylation and histone deacetylation, have not been thoroughly investigated in brain tumors, and elucidating such changes is likely to enhance our understanding of their etiology and provide new treatment options. We used a combined approach of pharmacologic inhibition of DNA methylation and histone deacetylation, coupled with expression microarrays, to identify novel targets of epigenetic silencing in glioma cell lines. From this analysis, we identified >160 genes up-regulated by 5-aza-2'-deoxycytidine and trichostatin A treatment. Further characterization of 10 of these genes, including the putative metastasis suppressor CST6, the apoptosis-inducer BIK, and TSPYL5, whose function is unknown, revealed that they are frequent targets of epigenetic silencing in glioma cell lines and primary tumors and suppress glioma cell growth in culture. Furthermore, we show that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant promoter hypermethylation events. These studies, therefore, lay the foundation for a comprehensive understanding of the full extent of epigenetic changes in gliomas and how they may be exploited for therapeutic purposes.


systematic_name: M12403
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE4554
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes discriminating between MSI (microsatellite instability) and MSS (microsatellite stability) colon cancers.

description_full:
  Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.


systematic_name: M8976
exact_source: Table 2S
source_species_code: HS
GEO_id: GSE4554
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes discriminating between MSI (microsatellite instability) and MSS (microsatellite stability) colon cancers.

description_full:
  Promoter methylation of the mismatch repair gene plays a key role in sporadic microsatellite instability (MSI) colorectal cancers. However, promoter methylation often occurs in proximal colon cancers, and molecular phenotypes underlying MSI cancers in distal colon have not been fully clarified. Our goal was to clarify the difference between MSI and microsatellite stability (MSS) cancers and, furthermore, to determine distinct characteristics of proximal and distal MSI cancers. By DNA microarray analysis of 84 cancers (33 MSI and 51 MSS), we identified discriminating genes (177 probe sets), which predicted MSI status with a high accuracy rate (97.6%). These genes were related to phenotypic characteristics of MSI cancers. Next, we identified 24 probe sets that were differentially expressed in proximal and distal MSI cancers. These genes included promoter methylation-mediated genes, whose expression was significantly down-regulated in proximal MSI cancers. Among discriminating genes between MSI and MSS, nine methylation-mediated genes showed down-regulation in MSI cancers. Of these, 7 (77.8%) showed down-regulation in proximal MSI cancers. Furthermore, methylation-specific PCR confirmed that frequency of hMLH1 promoter methylation was significantly higher in proximal MSI cancers (P = 0.0317). These results suggested that there is a difference between proximal and distal MSI cancers in methylation-mediated influence on gene silencing. In conclusion, using DNA microarray, we could distinguish MSI and MSS cancers. We also showed distinct characteristics of proximal and distal MSI cancers. The inactivation form of hMLH, per se, differed between proximal and distal MSI cancers. These results suggested that distal MSI cancers constitute a distinct subgroup of sporadic MSI cancers.


systematic_name: M7331
exact_source: Table 1: Up-regulated genes
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in H1975 cells (non-small cell lung cancer, NSCLC) resistant to gefitinib [PubChem=123631] after treatment with EGFR inhibitor CL-387785 [PubChem=2776] for 6h.

description_full:
  Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain determine responsiveness to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer (NSCLC). The modulation of transcriptional pathways by mutant EGFR signaling is not fully understood. Previously, we and others identified a single base pair change leading to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR as a common mechanism of acquired resistance. The gefitinib-resistant, T790M-mutant H1975 NSCLC cell line undergoes prominent growth arrest and apoptosis when treated with the irreversible EGFR inhibitor, CL-387,785. We did a transcriptional profiling study of mutant EGFR target genes that are differentially expressed in the resistant gefitinib-treated and the sensitive CL387,785-treated H1975 cells to identify the pivotal transcriptional changes in NSCLC with EGFR-activating mutations. We identified a small subset of early gene changes, including significant reduction of cyclin D1 as a result of EGFR inhibition by CL-387,785 but not by gefitinib. The reduction in cyclin D1 transcription was associated with subsequent suppression of E2F-responsive genes, consistent with proliferation arrest. Furthermore, cyclin D1 expression was higher in EGFR-mutant lung cancer cells compared with cells with wild-type EGFR. EGFR-mutant cells were routinely sensitive to the cyclin-dependent kinase inhibitor flavopiridol, confirming the functional relevance of the cyclin D axis. These studies suggest that cyclin D1 may contribute to the emergence of EGFR-driven tumorigenesis and can be an alternative target of therapy.


systematic_name: M8077
exact_source: Table 1S: d-stat < 0
source_species_code: HS
GEO_id: GSE2990
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes whose expression correlated with histologic grade of invasive breast cancer tumors: comparison of grade 1 vs grade 3.

description_full:
  BACKGROUND: Histologic grade in breast cancer provides clinically important prognostic information. However, 30%-60% of tumors are classified as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profiles of breast cancers and whether such profiles could be used to improve histologic grading. METHODS: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identified differentially expressed genes in a training set of 64 estrogen receptor (ER)-positive tumor samples by comparing expression profiles between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to define the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan-Meier analysis. All statistical tests were two-sided. RESULTS: We identified 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1-3 tumors. Among patients with histologic grade 2 tumors, a high gene expression grade index was associated with a higher risk of recurrence than a low gene expression grade index (hazard ratio = 3.61, 95% confidence interval = 2.25 to 5.78; P < .001, log-rank test). CONCLUSIONS: Gene expression grade index appeared to reclassify patients with histologic grade 2 tumors into two groups with high versus low risks of recurrence. This approach may improve the accuracy of tumor grading and thus its prognostic value.


systematic_name: M19107
exact_source: Table 1S: M population: f.ch.>0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in myeloid progenitor cells isolated from bone marrow of patients with Diamond-Blackfan anemia (DBA) and mutated RPS19 [GeneID=6223].

description_full:
  Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in approximately 25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.


systematic_name: M6979
exact_source: Table 1S: M population: f.ch.<0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in myeloid progenitor cells isolated from bone marrow of patients with Diamond-Blackfan anemia (DBA) and mutated RPS19 [GeneID=6223].

description_full:
  Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in approximately 25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.


systematic_name: M6984
exact_source: Table 1S: P population: f.ch.>0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in common hematopoietic progenitor cells isolated from bone marrow of patients with Diamond-Blackfan anemia (DBA) and mutated RPS19 [GeneID=6223].

description_full:
  Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in approximately 25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.


systematic_name: M12812
exact_source: Table 1S: P population: f.ch.<0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in common hematopoietic progenitor cells isolated from bone marrow of patients with Diamond-Blackfan anemia (DBA) and mutated RPS19 [GeneID=6223].

description_full:
[cell repeats an earlier one in this file: 1452 characters]


description_brief: Genes up-regulated in A549 cells (lung cancer) after knockdown of ATF4 [GeneID=468] by RNAi.
systematic_name: M10762
exact_source: Suppl. info: fold change > 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.


systematic_name: M3988
exact_source: Table S1: Fold change < 1 (green)
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in 3 out of 4 NSCLC cell lines (non-small cell lung cancer) after treatment with azacitidine [PubChem=9444] and TSA [PubChem=5562].

description_full:
  Lung cancer is the leading cause of cancer-related deaths in the United States due, in large part, to the lack of early detection methods. Lung cancer arises from a complex series of genetic and epigenetic changes leading to uncontrolled cell growth and metastasis. Unlike genetic changes, epigenetic changes, such as DNA methylation and histone acetylation, are reversible with currently available pharmaceuticals and are early events in lung tumorigenesis detectable by non-invasive methods. In order to better understand how epigenetic changes contribute to lung cancer, and to identify new disease biomarkers, we combined pharmacologic inhibition of DNA methylation and histone deacetylation in non-small cell lung cancer (NSCLC) cell lines, with genome-wide expression profiling. Of the more than 200 genes upregulated by these treatments, three of these, neuronatin, metallothionein 3 and cystatin E/M, were frequently hypermethylated and transcriptionally downregulated in NSCLC cell lines and tumors. Interestingly, four other genes, cylindromatosis, CD9, activating transcription factor 3 and oxytocin receptor, were dominantly regulated by histone deacetylation and were also frequently downregulated in lung tumors. The majority of these genes also suppressed NSCLC growth in culture when ectopically expressed. This study therefore reveals new putative NSCLC growth regulatory genes and epigenetic disease biomarkers that may enhance early detection strategies and serve as therapeutic targets.


systematic_name: M2012
exact_source: Table 2S: Mean Fold-Difference > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in mARMS (molecular ARMS) compared to the mERMS (molecular ERMS) class of rhabdomyosarcoma tumors.

description_full:
  Alveolar rhabdomyosarcomas (ARMS) are aggressive soft-tissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.


systematic_name: M4680
exact_source: Table 3S: Mean Fold-Difference > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in RD cells (embryonal rhabdomyosarcoma, ERMS) by expression of PAX3- or PAX7-FOXO1 [GeneID=5077;5081;2308] fusions off retroviral vectors.

description_full:
[cell repeats an earlier one in this file: 1766 characters]


systematic_name: M4001
exact_source: Table 3S: Mean Fold-Difference < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in RD cells (embryonal rhabdomyosarcoma, ERMS) by expression of PAX3- or PAX7-FOXO1 [GeneID=5077;5081;2308] fusions off retroviral vectors.

description_full:
[cell repeats an earlier one in this file: 1766 characters]


systematic_name: M12362
exact_source: Table 4S: Mean Fold-Difference > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in RMS cells (rhabdomyosarcoma) expressing PAX3 or PAX7 fusions with FOXO1 [GeneID=5077;5081;2308] compared to the fusion negative cell lines.

description_full:
[cell repeats an earlier one in this file: 1766 characters]


systematic_name: M1614
exact_source: Table 4S: Mean Fold-Difference < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in RMS cells (rhabdomyosarcoma) expressing PAX3 or PAX7 fusions with FOXO1 [GeneID=5077;5081;2308] compared to the fusion negative cell lines.

description_full:
[cell repeats an earlier one in this file: 1766 characters]


systematic_name: M6750
exact_source: Table 9S
source_species_code: HS
GEO_id: GSE12452
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in nasopharyngeal carcinoma (NPC) positive for LMP1 [GeneID=9260], a latent gene of Epstein-Barr virus (EBV).

description_full:
  To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.


description_brief: Genes up-regulated in normal ductal and normal lobular breast cells.
systematic_name: M2204
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE5764
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  BACKGROUND: Invasive ductal and lobular carcinomas (IDC and ILC) are the most common histological types of breast cancer. Clinical follow-up data and metastatic patterns suggest that the development and progression of these tumors are different. The aim of our study was to identify gene expression profiles of IDC and ILC in relation to normal breast epithelial cells. METHODS: We examined 30 samples (normal ductal and lobular cells from 10 patients, IDC cells from 5 patients, ILC cells from 5 patients) microdissected from cryosections of ten mastectomy specimens from postmenopausal patients. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. Samples were analysed upon Affymetrix U133 Plus 2.0 Arrays. The expression of seven differentially expressed genes (CDH1, EMP1, DDR1, DVL1, KRT5, KRT6, KRT17) was verified by immunohistochemistry on tissue microarrays. Expression of ASPN mRNA was validated by in situ hybridization on frozen sections, and CTHRC1, ASPN and COL3A1 were tested by PCR. RESULTS: Using GCOS pairwise comparison algorithm and rank products we have identified 84 named genes common to ILC versus normal cell types, 74 named genes common to IDC versus normal cell types, 78 named genes differentially expressed between normal ductal and lobular cells, and 28 named genes between IDC and ILC. Genes distinguishing between IDC and ILC are involved in epithelial-mesenchymal transition, TGF-beta and Wnt signaling. These changes were present in both tumor types but appeared to be more prominent in ILC. Immunohistochemistry for several novel markers (EMP1, DVL1, DDR1) distinguished large sets of IDC from ILC. CONCLUSION: IDC and ILC can be differentiated both at the gene and protein levels. In this study we report two candidate genes, asporin (ASPN) and collagen triple helix repeat containing 1 (CTHRC1) which might be significant in breast carcinogenesis. Besides E-cadherin, the proteins validated on tissue microarrays (EMP1, DVL1, DDR1) may represent novel immunohistochemical markers helpful in distinguishing between IDC and ILC. Further studies with larger sets of patients are needed to verify the gene expression profiles of various histological types of breast cancer in order to determine molecular subclassifications, prognosis and the optimum treatment strategies.


description_brief: Top 50 genes up-regulated in metastatic vs primary prostate cancer tumors.
systematic_name: M18970
exact_source: Table 2
source_species_code: HS
GEO_id: GSE6919
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  BACKGROUND: Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. METHODS: Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. RESULTS: The metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). CONCLUSION: We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer.


description_brief: Genes down-regulated in macrophage by live P.gingivalis.
systematic_name: M14032
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Porphyromonas gingivalis (P. gingivalis) can trigger an inflammatory condition leading to the destruction of periodontal tissues. However P. gingivalis LPS and its fimbriae (FimA) play different roles compared with the live bacteria in the context of intracellular molecule induction and cytokine secretion. To elucidate whether this difference results from different signaling pathways in host immune response to P. gingivalis, its LPS, or its FimA, we examined gene expression profile of human macrophages exposed to P. gingivalis, its LPS, or its FimA. A comparison of gene expression resulted in the identification of three distinct groups of expressed genes. Furthermore, computer-assisted promoter analysis of a subset of each group of differentially regulated genes revealed four putative transcriptional regulation models that associate with transcription factors NFkappaB, IRF7, and KLF4. Using gene knockout mice and siRNA to silence mouse genes, we showed that both TLR2 and TLR7 are essential for the induction of NFkappaB-containing genes and NFkappaB-IFN-sensitive response element (ISRE) cocontaining genes by either P. gingivalis or its purified components. The gene induction via either TLR2 or TLR7 is dependent on both MyD88 and p38 MAPK. However, the unique induction of IFN-beta by P. gingivalis LPS requires TLR7 and IFNalphabetaR cosignaling, and the induction of ISRE-containing gene is dependent on the activation of IFN-beta autocrine loop. Taken together, these data demonstrate that P. gingivalis and its components induce NFkappaB-containing genes through either TLR2- or TLR7-MyD88-p38 MAPK pathway, while P. gingivalis LPS uniquely induces ISRE-containing genes, which requires IFNalphabetaR signaling involving IRF7, KLF4, and pY701 STAT1.


systematic_name: M13045
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE7554
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in 293 cells (embryonic kidney) upon expression of KHSV (Kaposi sarcoma-associated herpesvirus) microRNAs.

description_full:
  MicroRNAs (miRNAs) are 19 to 23 nucleotide-long RNAs that post-transcriptionally regulate gene expression. Human cells express several hundred miRNAs which regulate important biological pathways such as development, proliferation, and apoptosis. Recently, 12 miRNA genes have been identified within the genome of Kaposi sarcoma-associated herpesvirus; however, their functions are still unknown. To identify host cellular genes that may be targeted by these novel viral regulators, we performed gene expression profiling in cells stably expressing KSHV-encoded miRNAs. Data analysis revealed a set of 81 genes whose expression was significantly changed in the presence of miRNAs. While the majority of changes were below 2-fold, eight genes were down-regulated between 4- and 20-fold. We confirmed miRNA-dependent regulation for three of these genes and found that protein levels of thrombospondin 1 (THBS1) were decreased >10-fold. THBS1 has previously been reported to be down-regulated in Kaposi sarcoma lesions and has known activity as a strong tumor suppressor and anti-angiogenic factor, exerting its anti-angiogenic effect in part by activating the latent form of TGF-beta. We show that reduced THBS1 expression in the presence of viral miRNAs translates into decreased TGF-beta activity. These data suggest that KSHV-encoded miRNAs may contribute directly to pathogenesis by down-regulation of THBS1, a major regulator of cell adhesion, migration, and angiogenesis.


systematic_name: M17268
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE7554
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in 293 cells (embryonic kidney) upon expression of KHSV (Kaposi sarcoma-associated herpesvirus) microRNAs.

description_full:
  MicroRNAs (miRNAs) are 19 to 23 nucleotide-long RNAs that post-transcriptionally regulate gene expression. Human cells express several hundred miRNAs which regulate important biological pathways such as development, proliferation, and apoptosis. Recently, 12 miRNA genes have been identified within the genome of Kaposi sarcoma-associated herpesvirus; however, their functions are still unknown. To identify host cellular genes that may be targeted by these novel viral regulators, we performed gene expression profiling in cells stably expressing KSHV-encoded miRNAs. Data analysis revealed a set of 81 genes whose expression was significantly changed in the presence of miRNAs. While the majority of changes were below 2-fold, eight genes were down-regulated between 4- and 20-fold. We confirmed miRNA-dependent regulation for three of these genes and found that protein levels of thrombospondin 1 (THBS1) were decreased >10-fold. THBS1 has previously been reported to be down-regulated in Kaposi sarcoma lesions and has known activity as a strong tumor suppressor and anti-angiogenic factor, exerting its anti-angiogenic effect in part by activating the latent form of TGF-beta. We show that reduced THBS1 expression in the presence of viral miRNAs translates into decreased TGF-beta activity. These data suggest that KSHV-encoded miRNAs may contribute directly to pathogenesis by down-regulation of THBS1, a major regulator of cell adhesion, migration, and angiogenesis.


systematic_name: M8455
exact_source: Table S1: Fold change > 2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in PC-3 cells (prostate cancer) stably expressing ST7 [GeneID=7982] off a plasmid vector.

description_full:
  Multiple lines of evidence have provided compelling evidence for the existence of a tumor suppressor gene (TSG) on chromosome 7q31.1. ST7 may be the target of this genetic instability but its designation as a TSG is controversial. In this study, we show that, functionally, ST7 behaves as a tumor suppressor in human cancer. ST7 suppressed growth of PC-3 prostate cancer cells inoculated subcutaneously into severe combined immunodeficient mice, and increased the latency of tumor detection from 13 days in control tumors to 23 days. Re-expression of ST7 was also associated with suppression of colony formation under anchorage-independent conditions in MDA-MB-231 breast cancer cells and ST7 mRNA expression was downregulated in 44% of primary breast cancers. Expression profiling of PC-3 cells revealed that ST7 predominantly induces changes in genes involved in re-modeling the extracellular matrix such as SPARC, IGFBP5 and several matrix metalloproteinases. These data indicate that ST7 may mediate tumor suppression through modification of the tumor microenvironment.


systematic_name: M11665
exact_source: Table 1, 3
source_species_code: HS
GEO_id: GSE4225
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ACC3 cells (adenoid cystic carcinoma) after knockdown of SOX4 [GeneID=6659] by RNAi.

description_full:
  Microarray RNA gene expression profiling analysis has shown that Sox4 (Sry-related high mobility group (HMG) box 4) is one of the most upregulated genes in adenoid cystic carcinoma (ACC), relative to non-neoplastic tissue of origin. Here, we show that Sox4 protein is similarly upregulated in ACC by immunohistochemistry of 28 primary cancers and 20 normal tissues. To elucidate the functional significance of these findings, RNA interference (RNAi)-mediated RNA silencing was used to downregulate Sox4 expression in the ACC-derived cell line, ACC3. With confirmed knockdown of Sox4 protein, cell viability was reduced by 51%, with a corresponding increase of apoptosis to 85% as compared to 12% in controls. Apoptosis was confirmed by cell morphology, DNA fragmentation and flow cytometry. Cells could be rescued from the proapoptotic effects of Sox4 RNAi by co-transfection with a construct expressing functional Sox4. Microarray gene expression profiling of RNAi knockdown experiments shows that downregulation of Sox4-modulated expression of critical genes involved in apoptosis and cell cycle control. Overall, our findings suggest that Sox4 contributes to the malignant phenotype of ACC cells by promoting cell survival.


description_brief: Genes up-regulated in OV-90 cells (ovarian cancer) exposed to ascites which inhibited invasion.
systematic_name: M3737
exact_source: Table W1: Up
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  At least one third of all cases of epithelial ovarian cancer are associated with the production of ascites, although its effect on tumor cell microenvironment remains poorly understood. This study addresses the effect of the heterologous acellular fraction of ovarian cancer-derived ascites on a cell line (OV-90) derived from the chemotherapy-naïve ovarian cancer patient. Ascites were assayed for their effect on cell invasion, growth, and spheroid formation. When compared to either no serum or 5% serum, ascites fell into one of two categories: stimulatory or inhibitory. RNA from OV-90 cells exposed to selected ascites were arrayed on an Affymetrix HG-U133A GeneChip. A supervised analysis identified a number of differentially expressed genes and quantitative polymerase chain reaction validation based on OV-90 cells exposed to 54 independent ascites demonstrated that stimulatory ascites affected the expression of ISGF3G, TRIB1, MKP1, RGS4, PLEC1, and MOSPD1 genes. In addition, TRIB1 expression was shown to independently correlate with prognosis when its expression was ascertained in an independent set of primary cultures established from ovarian ascites. The data support the validity of the strategy to uncover molecular events that are associated with tumor cell behavior and highlight the impact of ascites on the cellular and molecular parameters of ovarian cancer.


systematic_name: M15008
exact_source: Table 1BS
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in U87 cells (glioblastoma multiforme, GBM) engineered to stably express LGI1 [GeneID=9211].

description_full:
  Disruptions of LGI1 in glioblastoma (GBM) cell lines and LGI1 mutations in families with autosomal dominant epilepsy imply a role for LGI1 in glial cells as well as in neurons. Although we and others could not find LGI1 mutations in malignant gliomas, our initial studies appeared to support the idea that LGI1 is poorly expressed or absent in these tumors. Microarray data suggested that LGI1 could be involved in the control of matrix metalloproteinases, and we found that tumors derived from U87 glioblastoma cells overexpressing LGI1 were less aggressive than U87 control tumors. To our surprise, we observed that LGI1 expression after differentiation of murine neural stem cells was robust in neurons but negligible in glial cells, in agreement with immunohistochemistry studies on rodent brain. This observation could suggest that the variable levels of LGI1 expression in gliomas reflect the presence of neurons entrapped within the tumor. To test this hypothesis, we investigated LGI1 expression in parallel with expression of the neuronal marker NEF3 by real-time PCR on 30 malignant gliomas. Results showed a strong, positive correlation between the expression levels of these two genes (P < 0.0001). Thus, our data confirm that LGI1 is involved in cell-matrix interactions but suggest that its expression is not relevant in glial cells, implying that its role as a tumor suppressor in gliomas should be reconsidered.


systematic_name: M2835
exact_source: Table 1AS
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in U87 cells (glioblastoma multiforme, GBM) engineered to stably express LGI1 [GeneID=9211].

description_full:
  Disruptions of LGI1 in glioblastoma (GBM) cell lines and LGI1 mutations in families with autosomal dominant epilepsy imply a role for LGI1 in glial cells as well as in neurons. Although we and others could not find LGI1 mutations in malignant gliomas, our initial studies appeared to support the idea that LGI1 is poorly expressed or absent in these tumors. Microarray data suggested that LGI1 could be involved in the control of matrix metalloproteinases, and we found that tumors derived from U87 glioblastoma cells overexpressing LGI1 were less aggressive than U87 control tumors. To our surprise, we observed that LGI1 expression after differentiation of murine neural stem cells was robust in neurons but negligible in glial cells, in agreement with immunohistochemistry studies on rodent brain. This observation could suggest that the variable levels of LGI1 expression in gliomas reflect the presence of neurons entrapped within the tumor. To test this hypothesis, we investigated LGI1 expression in parallel with expression of the neuronal marker NEF3 by real-time PCR on 30 malignant gliomas. Results showed a strong, positive correlation between the expression levels of these two genes (P < 0.0001). Thus, our data confirm that LGI1 is involved in cell-matrix interactions but suggest that its expression is not relevant in glial cells, implying that its role as a tumor suppressor in gliomas should be reconsidered.


description_brief: Genes down-regulated in samples with systolic heart failure compared to normal hearts.
systematic_name: M18441
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  BACKGROUND: Chronic heart failure is characterized by left ventricular remodeling and reactivation of a fetal gene program; the underlying mechanisms are only partly understood. Here we provide evidence that cardiac microRNAs, recently discovered key regulators of gene expression, contribute to the transcriptional changes observed in heart failure. METHODS AND RESULTS: Cardiac transcriptome analyses revealed striking similarities between fetal and failing human heart tissue. Using microRNA arrays, we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. Bioinformatic analysis demonstrated a striking concordance between regulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3' untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy as well as changes in gene expression comparable to the failing heart. CONCLUSIONS: Our data support a novel mode of regulation for the transcriptional changes in cardiac failure. Reactivation of a fetal microRNA program substantially contributes to alterations of gene expression in the failing human heart.


description_brief: Genes up-regulated in multiple myeloma (MM) bone marrow mesenchymal stem cells.
systematic_name: M13639
exact_source: Table 1S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Recent literature suggested that cells of the microenvironment of tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression profiling and phenotypic and functional studies in three groups of individuals: patients with MM, patients with monoclonal gamopathy of undefined significance (MGUS) and healthy age-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in an MM group. MGUS BMMSCs were interspersed between these two groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs, 46% may account for a tumor-microenvironment cross-talk. Known soluble factors implicated in MM pathophysiologic features (i.e. IL (interleukin)-6, DKK1) were revealed and new ones were found which are involved in angiogenesis, osteogenic differentiation or tumor growth. In particular, GDF15 was found to induce dose-dependent growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an overgrowth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, MM BMMSCs are abnormal and could create a very efficient niche to support the survival and proliferation of the myeloma cells.


systematic_name: M12653
exact_source: Table 3S: Fold change =< 0.5
source_species_code: HS
GEO_id: GSE4392
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in B-CLL (B-cell chronic leukemia) patients expressing high levels of ZAP70 and CD38 [GeneID=7535;952], which are associated with poor survival.

description_full:
  B-cell chronic lymphocytic leukaemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of zeta-associated protein 70 (ZAP-70) and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70-CD38-) and poor (ZAP-70+CD38+) prognosis. DNA microarray technology was employed to compare eight ZAP-70+CD38+ with eight ZAP-70-CD38- B-CLL cases. The expression of 358 genes differed significantly between the two subgroups, including genes involved in B-cell receptor signaling, angiogenesis and lymphomagenesis. Three of these genes, that is, immune receptor translocation-associated protein 4 (IRTA4)/Fc receptor homologue 2 (FcRH2), angiopoietin 2 (ANGPT2) and Pim2 were selected for further validating studies in a cohort of 94 B-CLL patients. IRTA4/FcRH2 expression as detected by flow cytometry was significantly lower in the poor prognosis subgroup as compared to ZAP-70-CD38- B-CLL cells. In healthy individuals, IRTA4/FcRH2 protein expression was associated with a CD19+CD27+ memory cell phenotype. ANGPT2 plasma concentrations were twofold higher in the poor prognosis subgroup (P<0.05). Pim2 was significantly overexpressed in poor prognosis cases and Binet stage C. Disease progression may be related to proangiogenic processes and strong Pim2 expression.


description_brief: Genes up-regulated in secondary APL (acute promyelocytic leukemia) compared to the de novo tumors.
systematic_name: M13339
exact_source: Table 2: upregulated in sAPL
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Acute promyelocytic leukemia (APL) is a clonal expansion of hematopoietic precursors blocked at the promyelocytic stage. Gene expression profiles of APL cells obtained from 16 patients were compared to eight samples of CD34+-derived normal promyelocytes. Malignant promyelocytes showed widespread changes in transcription in comparison to their normal counterpart and 1020 differentially expressed genes were identified. Discriminating genes include transcriptional regulators (FOS, JUN and HOX genes) and genes involved in cell cycle and DNA repair. The strong upregulation in APL of some transcripts (FLT3, CD33, CD44 and HGF) was also confirmed at protein level. Interestingly, a trend toward a transcriptional repression of genes involved in different DNA repair pathways was found in APL and confirmed by real-time polymerase chain reactor (PCR) in a new set of nine APLs. Our results suggest that both inefficient base excision repair and recombinational repair might play a role in APLs development. To investigate the expression pathways underlying the development of APL occurring as a second malignancy (sAPL), we included in our study eight cases of sAPL. Although both secondary and de novo APL were characterized by a strong homogeneity in expression profiling, we identified a small set of differentially expressed genes that discriminate sAPL from de novo cases.


systematic_name: M16431
exact_source: Table 2AS: Ratio (T-PLL/ND) >= 2
source_species_code: HS
GEO_id: GSE5788
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in T-PLL cells (T-cell prolymphocytic leukemia) bearing the inv(14)/t(14:14) chromosomal aberration.

description_full:
  T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive lymphoma derived from mature T cells, which is, in most cases, characterized by the presence of an inv(14)(q11q32)/t(14;14)(q11;q32) and a characteristic pattern of secondary chromosomal aberrations. DNA microarray technology was employed to compare the transcriptomes of eight immunomagnetically purified CD3+ normal donor-derived peripheral blood cell samples, with five highly purified inv(14)/t(14;14)-positive T-PLL blood samples. Between the two experimental groups, 734 genes were identified as differentially expressed, including functionally important genes involved in lymphomagenesis, cell cycle regulation, apoptosis and DNA repair. Notably, the differentially expressed genes were found to be significantly enriched in genomic regions affected by recurrent chromosomal imbalances. Upregulated genes clustered on chromosome arms 6p and 8q, and downregulated genes on 6q, 8p, 10p, 11q and 18p. High-resolution copy-number determination using single nucleotide polymorphism chip technology in 12 inv(14)/t(14;14)-positive T-PLL including those analyzed for gene expression, refined chromosomal breakpoints as well as regions of imbalances. In conclusion, combined transcriptional and molecular cytogenetic profiling identified novel specific chromosomal loci and genes that are likely to be involved in disease progression and suggests a gene dosage effect as a pathogenic mechanism in T-PLL.


systematic_name: M15066
exact_source: Table 1S: average (cMyb/Cont) >= 2
source_species_code: HS
GEO_id: GSE2816,GSE2815
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) by overexpression of CMYB [GeneID=4602] off adenovirus vector.

description_full:
  The v-Myb oncoprotein encoded by Avian Myeloblastosis Virus is highly oncogenic, induces leukemias in chickens and mice and transforms immature hematopoietic cells in vitro. The v-Myb protein is a mutated and truncated version of c-Myb, a DNA-binding transcription factor expressed in many cell types that is essential for normal hematopoiesis. Previous studies suggested that two types of differences, DNA binding domain mutations and the deletion of a C-terminal negative regulatory domain were important for increasing the transforming activity of v-Myb. Here, we combined structure-function studies of the v-Myb and c-Myb proteins with unbiased microarray-based transcription assays to compare the transcriptional specificities of the two proteins. In human cells, the v-Myb and c-Myb proteins displayed strikingly different activities and regulated overlapping, but largely distinct sets of target genes. Each type of mutation that distinguished v-Myb from c-Myb, including the N- and C-terminal deletions, DNA binding domain changes and mutations in the transcriptional activation domain, affected different sets of target genes and contributed to the different activities of c-Myb and v-Myb. The results suggest that v-Myb is not just a de-repressed version of c-Myb. Instead, it is a distinct transcriptional regulator with a unique set of activities.


systematic_name: M9230
exact_source: Table 1S: average (cMyb/Cont) <= 0.5
source_species_code: HS
GEO_id: GSE2816,GSE2815
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF-7 cells (breast cancer) by overexpression of CMYB [GeneID=4602] off adenovirus vector.

description_full:
  The v-Myb oncoprotein encoded by Avian Myeloblastosis Virus is highly oncogenic, induces leukemias in chickens and mice and transforms immature hematopoietic cells in vitro. The v-Myb protein is a mutated and truncated version of c-Myb, a DNA-binding transcription factor expressed in many cell types that is essential for normal hematopoiesis. Previous studies suggested that two types of differences, DNA binding domain mutations and the deletion of a C-terminal negative regulatory domain were important for increasing the transforming activity of v-Myb. Here, we combined structure-function studies of the v-Myb and c-Myb proteins with unbiased microarray-based transcription assays to compare the transcriptional specificities of the two proteins. In human cells, the v-Myb and c-Myb proteins displayed strikingly different activities and regulated overlapping, but largely distinct sets of target genes. Each type of mutation that distinguished v-Myb from c-Myb, including the N- and C-terminal deletions, DNA binding domain changes and mutations in the transcriptional activation domain, affected different sets of target genes and contributed to the different activities of c-Myb and v-Myb. The results suggest that v-Myb is not just a de-repressed version of c-Myb. Instead, it is a distinct transcriptional regulator with a unique set of activities.


systematic_name: M1584
exact_source: Table 1S: average (vMyb/Cont) >= 2
source_species_code: HS
GEO_id: GSE2816,GSE2815
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF-7 cells (breast cancer) by overexpression of v-MYB oncogenic varian of CMYB [GeneID=4602] off adenovirus vector.

description_full:
  The v-Myb oncoprotein encoded by Avian Myeloblastosis Virus is highly oncogenic, induces leukemias in chickens and mice and transforms immature hematopoietic cells in vitro. The v-Myb protein is a mutated and truncated version of c-Myb, a DNA-binding transcription factor expressed in many cell types that is essential for normal hematopoiesis. Previous studies suggested that two types of differences, DNA binding domain mutations and the deletion of a C-terminal negative regulatory domain were important for increasing the transforming activity of v-Myb. Here, we combined structure-function studies of the v-Myb and c-Myb proteins with unbiased microarray-based transcription assays to compare the transcriptional specificities of the two proteins. In human cells, the v-Myb and c-Myb proteins displayed strikingly different activities and regulated overlapping, but largely distinct sets of target genes. Each type of mutation that distinguished v-Myb from c-Myb, including the N- and C-terminal deletions, DNA binding domain changes and mutations in the transcriptional activation domain, affected different sets of target genes and contributed to the different activities of c-Myb and v-Myb. The results suggest that v-Myb is not just a de-repressed version of c-Myb. Instead, it is a distinct transcriptional regulator with a unique set of activities.


systematic_name: M3389
exact_source: Table 4S: Heat Map Order 1-27
source_species_code: HS
GEO_id: GSE2816,GSE2815
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes regulated in the opposite directions by v-MYB (UP) and c-MYB  (DN) variants of CMYB [GeneID=4602] overexpressed in primary monocyte cultures off adenoviral vectors.

description_full:
[cell repeats an earlier one in this file: 1359 characters]


systematic_name: M3258
exact_source: Table 4S: Heat Map Order 28-82
source_species_code: HS
GEO_id: GSE2816,GSE2815
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Gene regulated in the opposite directions by v-MYB (DN) and c-MYB  (UP) variants of CMYB [GeneID=4602] overexpressed in primary monocyte cultures off adenoviral vectors.

description_full:
[cell repeats an earlier one in this file: 1359 characters]


systematic_name: M12895
exact_source: Table 4S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in basal-like breast cancer cell lines as compared to the mesenchymal-like ones.

description_full:
  A better molecular characterization of breast cell lines (BCL) may help discover new markers to apply to tumour samples. We performed gene and protein expression profiling of 31 BCL using whole-genome DNA microarrays and immunohistochemistry (IHC) on 'cell microarrays' (CMA), respectively. Global hierarchical clustering discriminated two groups of BCL: group I corresponded to luminal cell lines, group II to basal and mesenchymal cell lines. Correlations with centroids calculated from a published 'intrinsic 500-gene set' assigned 15 cell lines as luminal, eight as basal and four as mesenchymal. A set of 1.233 genes was differentially expressed between basal and luminal samples. Mesenchymal and basal subtypes were rather similar and discriminated by only 227 genes. The expression of 10 proteins (CAV1, CD44, EGFR, MET, ETS1, GATA3, luminal cytokeratin CK19, basal cytokeratin CK5/6, CD10, and ERM protein moesin) encoded by luminal vs basal discriminator genes confirmed the subtype classification and the validity of the identified markers. Our BCL basal/luminal signature correctly re-classified the published series of tumour samples that originally served to identify the molecular subtypes, suggesting that the identified markers should be useful for tumour classification and might represent promising targets for disease management.


systematic_name: M11771
exact_source: Table 1: Class A v B Fold Change < 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ER(-) / PR(-) breast tumors (do not express ESR1 and PGR [GeneID=2099;5241]) with molecular similarity to ER(+) (class A) relative to the rest of the ER(-) / PR(-) samples (class B).

description_full:
  Little is known of the underlying biology of estrogen receptor-negative, progesterone receptor-negative (ER(-)/PR(-)) breast cancer (BC), and few targeted therapies are available. Clinical heterogeneity of ER(-)/PR(-) tumors suggests that molecular subsets exist. We performed genome-wide expression analysis of 99 primary BC samples and eight BC cell lines in an effort to reveal distinct subsets, provide insight into their biology and potentially identify new therapeutic targets. We identified a subset of ER(-)/PR(-) tumors with paradoxical expression of genes known to be either direct targets of ER, responsive to estrogen, or typically expressed in ER(+) BC. Differentially expressed genes included SPDEF, FOXA1, XBP1, CYB5, TFF3, NAT1, APOD, ALCAM and AR (P<0.001). A classification model based on the expression signature of this tumor class identified molecularly similar BCs in an independent human BC data set and among BC cell lines (MDA-MB-453). This cell line demonstrated a proliferative response to androgen in an androgen receptor-dependent and ER-independent manner. In addition, the androgen-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of the unique ER(-)/PR(-) subclass of human tumors. This subset of BCs, characterized by a hormonally regulated transcriptional program and response to androgen, suggests the potential for therapeutic strategies targeting the androgen signaling pathway.


systematic_name: M8570
exact_source: Table 2S: Up in ER N.txt
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in breast cancer samples positive for ESR1 [GeneID=2099] compared to the ESR1 negative tumors.

description_full:
  Little is known of the underlying biology of estrogen receptor-negative, progesterone receptor-negative (ER(-)/PR(-)) breast cancer (BC), and few targeted therapies are available. Clinical heterogeneity of ER(-)/PR(-) tumors suggests that molecular subsets exist. We performed genome-wide expression analysis of 99 primary BC samples and eight BC cell lines in an effort to reveal distinct subsets, provide insight into their biology and potentially identify new therapeutic targets. We identified a subset of ER(-)/PR(-) tumors with paradoxical expression of genes known to be either direct targets of ER, responsive to estrogen, or typically expressed in ER(+) BC. Differentially expressed genes included SPDEF, FOXA1, XBP1, CYB5, TFF3, NAT1, APOD, ALCAM and AR (P<0.001). A classification model based on the expression signature of this tumor class identified molecularly similar BCs in an independent human BC data set and among BC cell lines (MDA-MB-453). This cell line demonstrated a proliferative response to androgen in an androgen receptor-dependent and ER-independent manner. In addition, the androgen-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of the unique ER(-)/PR(-) subclass of human tumors. This subset of BCs, characterized by a hormonally regulated transcriptional program and response to androgen, suggests the potential for therapeutic strategies targeting the androgen signaling pathway.


systematic_name: M2849
exact_source: Table 1S: fold change < 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in SK-NEP-1 cells (Wilm's tumor ) stably expressing inactivated forms of STAT1 [GeneID=6772] under growth stress (hypoxia or nutritional deprivation).

description_full:
  Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3'-kinase, protein kinase C or Ca/calmodulin-dependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.


description_brief: Genes up-regulated in serrated vs conventional colorectal carcinoma (CRC) samples.
systematic_name: M16586
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE4045
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.


systematic_name: M7988
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in biphasic (mixed) vs epithelial subtypes of malignant peritoneal mesothelioma.

description_full:
  Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin-proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin-proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.


description_brief: Genes down-regulated in blood vessel cells from wound site.
systematic_name: M2176
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Chronic wounds represent a substantial public health problem. The development of tools that would enable sophisticated scrutiny of clinical wound tissue material is highly desirable. This work presents evidence enabling rapid specific identification and laser capture of blood vessels from human tissue in a manner which lends itself to successful high-density (U133A) microarray analysis. Such screening of transcriptome followed by real-time PCR and immunohistochemical verification of candidate genes and their corresponding products were performed by using 3 mm biopsies. Of the 18,400 transcripts and variants screened, a focused set of 53 up-regulated and 24 down-regulated genes were noted in wound-derived blood vessels compared with blood vessels from intact human skin. The mean abundance of periostin in wound-site blood vessels was 96-fold higher. Periostin is known to be induced in response to vascular injury and its expression is associated with smooth muscle cell differentiation in vitro and promotes cell migration. Forty-fold higher expression of heparan sulfate 6-O-endosulfatase1 (Sulf1) was noted in wound-site vessels. Sulf1 has been recently recognized to be anti-angiogenic. During embryonic vasculogenesis, CD24 expression is down-regulated in human embryonic stem cells. Wound-site vessels had lower CD24 expression. The findings of this work provide a unique opportunity to appreciate the striking contrast in the transcriptome composition in blood vessels collected from the intact skin and from the wound-edge tissue. Sets of genes with known vascular functions but never connected to wound healing were identified to be differentially expressed in wound-derived blood vessels paving the way for innovative clinically relevant hypotheses.


systematic_name: M6222
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Jurkat cells (transformed T lymphocytes) after knockdown of BCL11B [GeneID=64919] by RNAi.

description_full:
  The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Krüppel-like zinc-finger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumor-suppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Suppression of Bcl11b by RNA interference selectively induced apoptosis in transformed T cells whereas normal mature T cells remained unaffected. The apoptosis was effected by simultaneous activation of death receptor-mediated and intrinsic apoptotic pathways, most likely as a result of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) upregulation and suppression of the Bcl-xL antiapoptotic protein. Our data indicate an antiapoptotic function of Bcl11b. The resistance of normal mature T lymphocytes to Bcl11b suppression-induced apoptosis and restricted expression pattern make it an attractive therapeutic target in T-cell malignancies.


systematic_name: M19457
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Jurkat cells (transformed T lymphocytes) after knockdown of BCL11B [GeneID=64919] by RNAi.

description_full:
  The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Krüppel-like zinc-finger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumor-suppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Suppression of Bcl11b by RNA interference selectively induced apoptosis in transformed T cells whereas normal mature T cells remained unaffected. The apoptosis was effected by simultaneous activation of death receptor-mediated and intrinsic apoptotic pathways, most likely as a result of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) upregulation and suppression of the Bcl-xL antiapoptotic protein. Our data indicate an antiapoptotic function of Bcl11b. The resistance of normal mature T lymphocytes to Bcl11b suppression-induced apoptosis and restricted expression pattern make it an attractive therapeutic target in T-cell malignancies.


systematic_name: M17428
exact_source: Table 4S: Over expressed lists
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in leukemic stem cells (LSC), defined as CD34+CD38- [GeneID=947;952] cells from AML (acute myeloid leukemia patients) compared to the CD34+CD38+ cells.

description_full:
  Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34(+)CD38(-) cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34(+)CD38(-) cell fraction from AML and compared their gene expression profiles to the CD34(+)CD38(+) cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy.


description_brief: Genes down-regulated in adult T-cell leukemia (ATL), chronic vs acute clinical condition.
systematic_name: M609
exact_source: Table 2S: up in acute
source_species_code: HS
GEO_id: GSE1466
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Adult T-cell leukemia (ATL) is an intractable malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type I. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. To clarify the mechanism responsible for this stage progression, we isolated CD4+ cells from individuals in the chronic (n=19) or acute (n=22) stages of ATL and subjected them to profiling of gene expression with DNA microarrays containing >44,000 probe sets. Changes in chromosome copy number were also examined for 24 cell specimens with the use of microarrays harboring approximately 50,000 probe sets. Stage-dependent changes in gene expression profile and chromosome copy number were apparent. Furthermore, expression of the gene for MET, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was shown to be specific to the acute stage of ATL, and the plasma concentration of HGF was increased in individuals in either the acute or chronic stage. HGF induced proliferation of a MET-positive ATL cell line, and this effect was blocked by antibodies to HGF. The HGF-MET signaling pathway is thus a potential therapeutic target for ATL.


systematic_name: M14772
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Cellular proliferation, growth, apoptosis and Wnt signaling genes up-regulated in SNU638 cells (gastric cancer) by overexpression of SFRP2 [GeneID=6423] off a plasmid vector.

description_full:
  Activation of Wnt signaling has been implicated in gastric tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (beta-catenin) and AXIN are seen much less frequently in gastric cancer (GC) than in colorectal cancer. In the present study, we investigated the relationship between activation of Wnt signaling and changes in the expression of secreted frizzled-related protein (SFRP) family genes in GC. We frequently observed nuclear beta-catenin accumulation (13/15; 87%) and detected the active form of beta-catenin in most (12/16; 75%) GC cell lines. CpG methylation-dependent silencing of SFRP1, SFRP2 and SFRP5 was frequently seen among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/16, 100%; SFRP5, 13/16, 81%) and primary GC specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; SFRP5, 30/46, 65%), and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine rapidly restored SFRP expression. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor transcriptional activity, suppressed cell growth and induced apoptosis in GC cells. Analysis of global expression revealed that overexpression of SFRP2 repressed Wnt target genes and induced changes in the expression of numerous genes related to proliferation, growth and apoptosis in GC cells. It thus appears that aberrant SFRP methylation is one of the major mechanisms by which Wnt signaling is activated in GC.


description_brief: Genes positively correlated with the asbestos exposure of lung cancer patients.
systematic_name: M18658
exact_source: Table 1S: R > 0.8
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Asbestos is a pulmonary carcinogen known to give rise to DNA and chromosomal damage, but the exact carcinogenic mechanisms are still largely unknown. In this study, gene expression arrays were performed on lung tumor samples from 14 heavily asbestos-exposed and 14 non-exposed patients matched for other characteristics. Using a two-step statistical analysis, 47 genes were revealed that could differentiate the tumors of asbestos-exposed from those of non-exposed patients. To identify asbestos-associated regions with DNA copy number and expressional changes, the gene expression data were combined with comparative genomic hybridization microarray data. As a result, a combinatory profile of DNA copy number aberrations and expressional changes significantly associated with asbestos exposure was obtained. Asbestos-related areas were detected in 2p21-p16.3, 3p21.31, 5q35.2-q35.3, 16p13.3, 19p13.3-p13.1 and 22q12.3-q13.1. The most prominent of these, 19p13, was further characterized by microsatellite analysis in 62 patients for the differences in allelic imbalance (AI) between the two groups of lung tumors. 79% of the exposed and 45% of the non-exposed patients (P=0.008) were found to be carriers of AI in their lung tumors. In the exposed group, AI in 19p was prevalent regardless of the histological tumor type. In adenocarcinomas, AI in 19p appeared to occur independently of the asbestos exposure.


systematic_name: M18359
exact_source: Table 2S: Direction=I
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HCT8/S1 cells (colon cancer) which normally lack DCC [GeneID=9423] compared to those stably expressing wild type DCC off a plasmid vector.

description_full:
  Deleted in colon cancer (DCC) and UNC5 function as netrin dependence receptors by inducing apoptosis in the absence of their ligand and accordingly were recently designated as putative conditional tumor suppressors. Herein, we determined whether netrin-1 and its receptors are implicated in cancer cell invasion and tumor progression. Expression of DCC, UNC5 and adenosine A2B-receptors (A2B-Rs) was investigated by reverse transcription polymerase chain reaction in human colon cancer cells. The impact of DCC restitution and netrin-1 was evaluated on collagen type I invasion, tumor growth and metastasis in nude mice, cancer cell survival and gene expression profiling. Flow cytometry, poly(ADP-ribose)polymerase-1 and caspase-8 activation were used to evaluate the impact of DCC on cell death. Both netrin-1 and A2B-R activation induced the invasive phenotype through the Rho-Rho kinase axis in DCC-deficient human colorectal cancer cells. Restitution of wild-type DCC blocked invasion induced by netrin-1, A2B-R agonist and other agents. Ectopic expression of netrin-1 led to increased growth of human colon tumor xenografts in athymic mice. Conversely, introduction of wt-DCC in kidney MDCKts.src-ggl cells strongly inhibited metastasis in lymph nodes and lungs and increased sensitivity to apoptosis in hypoxia. DNA microarrays revealed that netrin and DCC had common and divergent impacts on gene expression linked to cell cycle, survival, surface signaling and adhesion. Our findings underscore that netrin is a potent invasion and tumor growth-promoting agent and that DCC is a metastasis suppressor gene targeting both proinvasive and survival pathways in a cumulative manner.


systematic_name: M12027
exact_source: Table 3S: Direction=I
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HCT8/S11 cells (colon cancer) engineered to stably express NTN1 [GeneID=1630] off a plasmid vector.

description_full:
  Deleted in colon cancer (DCC) and UNC5 function as netrin dependence receptors by inducing apoptosis in the absence of their ligand and accordingly were recently designated as putative conditional tumor suppressors. Herein, we determined whether netrin-1 and its receptors are implicated in cancer cell invasion and tumor progression. Expression of DCC, UNC5 and adenosine A2B-receptors (A2B-Rs) was investigated by reverse transcription polymerase chain reaction in human colon cancer cells. The impact of DCC restitution and netrin-1 was evaluated on collagen type I invasion, tumor growth and metastasis in nude mice, cancer cell survival and gene expression profiling. Flow cytometry, poly(ADP-ribose)polymerase-1 and caspase-8 activation were used to evaluate the impact of DCC on cell death. Both netrin-1 and A2B-R activation induced the invasive phenotype through the Rho-Rho kinase axis in DCC-deficient human colorectal cancer cells. Restitution of wild-type DCC blocked invasion induced by netrin-1, A2B-R agonist and other agents. Ectopic expression of netrin-1 led to increased growth of human colon tumor xenografts in athymic mice. Conversely, introduction of wt-DCC in kidney MDCKts.src-ggl cells strongly inhibited metastasis in lymph nodes and lungs and increased sensitivity to apoptosis in hypoxia. DNA microarrays revealed that netrin and DCC had common and divergent impacts on gene expression linked to cell cycle, survival, surface signaling and adhesion. Our findings underscore that netrin is a potent invasion and tumor growth-promoting agent and that DCC is a metastasis suppressor gene targeting both proinvasive and survival pathways in a cumulative manner.


systematic_name: M12674
exact_source: Figure 6S
source_species_code: HS
GEO_id: GSE7382
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer) engineered to conditionally express LMO4 [GeneID=8543] by a Tet Off system.

description_full:
  The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.


systematic_name: M8577
exact_source: Figure 7S
source_species_code: HS
GEO_id: GSE7382
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer) engineered to conditionally express a dominant negative form of CLIM2 [GeneID=8861] by a Tet Off system.

description_full:
  The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.


systematic_name: M2108
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes distinguishing between two subtypes of gastric cancer: advanced (AGC) and early (EGC).

description_full:
  Gastric carcinoma is one of the major causes of cancer mortality worldwide. Early detection results in excellent prognosis for patients with early cancer (EGC), whereas the prognosis of advanced cancer (AGC) patients remains poor. It is not clear whether EGC and AGC are molecularly distinct, and whether they represent progressive stages of the same tumor or different entities ab initio. Gene expression profiles of EGC and AGC were determined by Affymetrix technology and quantitative polymerase chain reaction. Representative regulated genes were further analysed by in situ hybridization (ISH) on tissue microarrays. Expression analysis allowed the identification of a signature that differentiates AGC from EGC. In addition, comparison with normal gastric mucosa indicated that the majority of alterations associated with EGC are retained in AGC, and that further expression changes mark the transition from EGC to AGC. Finally, ISH analysis showed that representative genes, differentially expressed in the invasive areas of EGC and AGC, are not differentially expressed in the non-invasive areas of the same tumors. Our data are more directly compatible with a progression model of gastric carcinogenesis, whereby EGC and AGC may represent different molecular stages of the same tumor. Finally, the identification of an AGC-specific signature might help devising novel therapeutic strategies for advanced gastric cancer.


systematic_name: M9728
exact_source: Table 4
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes from the 70-gene prognosis predictor for stage 2 colon cancer, based on non-neoplastic mucosa gene expression profiles.

description_full:
  We have assessed the possibility to build a prognosis predictor (PP), based on non-neoplastic mucosa microarray gene expression measures, for stage II colon cancer patients. Non-neoplastic colonic mucosa mRNA samples from 24 patients (10 with a metachronous metastasis, 14 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. Patients were repeatedly and randomly divided into 1000 training sets (TSs) of size 16 and validation sets (VS) of size 8. For each TS/VS split, a 70-gene PP, identified on the TS by selecting the 70 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Mean prognosis prediction performances of the 70-gene PP were 81.8% for accuracy, 73.0% for sensitivity and 87.1% for specificity. Informative genes suggested branching signal-transduction pathways with possible extensive networks between individual pathways. They also included genes coding for proteins involved in immune surveillance. In conclusion, our study suggests that one can build an accurate PP for stage II colon cancer patients, based on non-neoplastic mucosa microarray gene expression measures.


systematic_name: M5736
exact_source: Table 5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes from the 70-gene prognosis predictor for stage 2 colon cancer, based on non-neoplastic mucosa gene expression profiles.

description_full:
  We have assessed the possibility to build a prognosis predictor (PP), based on non-neoplastic mucosa microarray gene expression measures, for stage II colon cancer patients. Non-neoplastic colonic mucosa mRNA samples from 24 patients (10 with a metachronous metastasis, 14 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. Patients were repeatedly and randomly divided into 1000 training sets (TSs) of size 16 and validation sets (VS) of size 8. For each TS/VS split, a 70-gene PP, identified on the TS by selecting the 70 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Mean prognosis prediction performances of the 70-gene PP were 81.8% for accuracy, 73.0% for sensitivity and 87.1% for specificity. Informative genes suggested branching signal-transduction pathways with possible extensive networks between individual pathways. They also included genes coding for proteins involved in immune surveillance. In conclusion, our study suggests that one can build an accurate PP for stage II colon cancer patients, based on non-neoplastic mucosa microarray gene expression measures.


systematic_name: M15967
exact_source: Table 1BS: Log2 Ratio Mean(Cancer/Normal) < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in circulating endothelial cells (CEC) from cancer patients compared to those from healthy donors.

description_full:
  Increased numbers of endothelial cells are observed in peripheral blood of cancer patients. These circulating endothelial cells (CECs) may contribute to the formation of blood vessels in the tumor or reflect vascular damage caused by treatment or tumor growth. Characterization of these cells may aid in the understanding of the angiogenic process and may provide biomarkers for treatment efficacy of angiogenesis inhibitors. To identify markers typical for CECs in cancer patients, we assessed global gene expression profiles of CD146 immunomagnetically enriched CECs from healthy donors and patients with metastatic breast, colorectal, prostate, lung, and renal cancer. From the generated gene profiles, a list of 61 marker genes for CEC detection was generated, and their expression was measured by real-time quantitative PCR in blood samples from 81 metastatic cancer patients and 55 healthy donors that were immunomagnetically enriched for CECs. A set of 34 genes, among which novel CEC-associated genes, such as THBD, BST1, TIE1, POSTN1, SELE, SORT1, and DTR, were identified that were expressed at higher levels in cancer patients compared with healthy donors. Expression of the VWF, DTR, CDH5, TIE, and IGFBP7 genes were found to discriminate between cancer patients and healthy donors with a receiver operating characteristic curve accuracy of 0.93. Assessment of the expression of these genes may provide biomarkers to evaluate treatment efficacy.


description_brief: Genes up-regulated in metastases from malignant melanoma compared to the primary tumors.
systematic_name: M5740
exact_source: Table 2S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  PURPOSE: To better understand the molecular mechanisms of malignant melanoma progression and metastasis, gene expression profiling was done of primary melanomas and melanoma metastases. EXPERIMENTAL DESIGN: Tumor cell-specific gene expression in 19 primary melanomas and 22 melanoma metastases was analyzed using oligonucleotide microarrays after laser-capture microdissection of melanoma cells. Statistical analysis was done by random permutation analysis and support vector machines. Microarray data were further validated by immunohistochemistry and immunoblotting. RESULTS: Overall, 308 genes were identified that showed significant differential expression between primary melanomas and melanoma metastases (false discovery rate<or=0.05). Significantly overrepresented gene ontology categories in the list of 308 genes were cell cycle regulation, mitosis, cell communication, and cell adhesion. Overall, 47 genes showed up-regulation in metastases. These included Cdc6, Cdk1, septin 6, mitosin, kinesin family member 2C, osteopontin, and fibronectin. Down-regulated genes included E-cadherin, fibroblast growth factor binding protein, and desmocollin 1 and desmocollin 3, stratifin/14-3-3sigma, and the chemokine CCL27. Using support vector machine analysis of gene expression data, a performance of >85% correct classifications for primary melanomas and metastases was reached. Further analysis showed that subtypes of primary melanomas displayed characteristic gene expression patterns, as do thin tumors (<or=1.0 mm Breslow thickness) compared with intermediate and thick tumors (>2.0 mm Breslow thickness). CONCLUSIONS: Taken together, this large-scale gene expression study of malignant melanoma identified molecular signatures related to metastasis, melanoma subtypes, and tumor thickness. These findings not only provide deeper insights into the pathogenesis of melanoma progression but may also guide future research on innovative treatments.


systematic_name: M5827
exact_source: Table 4S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in non-metastatic breast cancer tumors having type 1 amplification in the 20q13 region; involves ZNF217 [GeneID=7764] locus only.

description_full:
  PURPOSE: Amplification of chromosomal region 20q13 occurs in breast cancer but remains poorly characterized. EXPERIMENTAL DESIGN: To establish the frequency of 20q13 amplification and select the amplified cases to be studied, we used fluorescence in situ hybridization of bacterial artificial chromosome probes for three 20q13 loci (MYBL2, STK6, ZNF217) on sections of tissue microarrays containing 466 primary carcinoma samples. We used Affymetryx whole-genome DNA microarrays to establish the gene expression profiles of 20q13-amplified tumors and quantitative reverse transcription-PCR to validate the results. RESULTS: We found 36 (8%) 20q13-amplified samples. They were distributed in two types: type 1 tumors showed ZNF217 amplification only, whereas type 2 tumors showed amplification at two or three loci. Examination of the histoclinical features of the amplified tumors showed two strikingly opposite data. First, type 1 tumors were more frequently lymph node-negative tumors but were paradoxically associated with a poor prognosis. Second, type 2 tumors were more frequently lymph node-positive tumors but were paradoxically associated with a good prognosis. Type 1 and type 2 showed different gene expression profiles. No 20q13 gene could be associated with type 1 amplification, whereas several 20q13 genes were overexpressed in type 2 tumors. CONCLUSIONS: Our results suggest that amplified tumors of types 1 and 2 are two distinct entities resulting from two different mechanisms and associated to different prognosis.


systematic_name: M17094
exact_source: Table 4S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in non-metastatic breast cancer tumors having type 1 amplification in the 20q13 region; involves ZNF217 [GeneID=7764] locus only.

description_full:
  PURPOSE: Amplification of chromosomal region 20q13 occurs in breast cancer but remains poorly characterized. EXPERIMENTAL DESIGN: To establish the frequency of 20q13 amplification and select the amplified cases to be studied, we used fluorescence in situ hybridization of bacterial artificial chromosome probes for three 20q13 loci (MYBL2, STK6, ZNF217) on sections of tissue microarrays containing 466 primary carcinoma samples. We used Affymetryx whole-genome DNA microarrays to establish the gene expression profiles of 20q13-amplified tumors and quantitative reverse transcription-PCR to validate the results. RESULTS: We found 36 (8%) 20q13-amplified samples. They were distributed in two types: type 1 tumors showed ZNF217 amplification only, whereas type 2 tumors showed amplification at two or three loci. Examination of the histoclinical features of the amplified tumors showed two strikingly opposite data. First, type 1 tumors were more frequently lymph node-negative tumors but were paradoxically associated with a poor prognosis. Second, type 2 tumors were more frequently lymph node-positive tumors but were paradoxically associated with a good prognosis. Type 1 and type 2 showed different gene expression profiles. No 20q13 gene could be associated with type 1 amplification, whereas several 20q13 genes were overexpressed in type 2 tumors. CONCLUSIONS: Our results suggest that amplified tumors of types 1 and 2 are two distinct entities resulting from two different mechanisms and associated to different prognosis.


systematic_name: M19076
exact_source: Table 5S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in metastatic breast cancer tumors having  type 2 amplification in the 20q13 region; involves MYBL2, STK6 and ZNF217 [GeneID=4605;6790;7764]

description_full:
  PURPOSE: Amplification of chromosomal region 20q13 occurs in breast cancer but remains poorly characterized. EXPERIMENTAL DESIGN: To establish the frequency of 20q13 amplification and select the amplified cases to be studied, we used fluorescence in situ hybridization of bacterial artificial chromosome probes for three 20q13 loci (MYBL2, STK6, ZNF217) on sections of tissue microarrays containing 466 primary carcinoma samples. We used Affymetryx whole-genome DNA microarrays to establish the gene expression profiles of 20q13-amplified tumors and quantitative reverse transcription-PCR to validate the results. RESULTS: We found 36 (8%) 20q13-amplified samples. They were distributed in two types: type 1 tumors showed ZNF217 amplification only, whereas type 2 tumors showed amplification at two or three loci. Examination of the histoclinical features of the amplified tumors showed two strikingly opposite data. First, type 1 tumors were more frequently lymph node-negative tumors but were paradoxically associated with a poor prognosis. Second, type 2 tumors were more frequently lymph node-positive tumors but were paradoxically associated with a good prognosis. Type 1 and type 2 showed different gene expression profiles. No 20q13 gene could be associated with type 1 amplification, whereas several 20q13 genes were overexpressed in type 2 tumors. CONCLUSIONS: Our results suggest that amplified tumors of types 1 and 2 are two distinct entities resulting from two different mechanisms and associated to different prognosis.


systematic_name: M19988
exact_source: Table 5S
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in metastatic breast cancer tumors having  type 2 amplification in the 20q13 region; involves MYBL2, STK6 and ZNF217 [GeneID=4605;6790;7764]

description_full:
[cell repeats an earlier one in this file: 1533 characters]


systematic_name: M1930
exact_source: Table 1S: module=yellow & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the yellow module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
  Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.


systematic_name: M10172
exact_source: Table 1S: module=yellow & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the yellow module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
  Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.


systematic_name: M18008
exact_source: Table 1S: module=red & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the red module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
  Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.


systematic_name: M168
exact_source: Table 1S: module=magenta & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the magenta module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M19724
exact_source: Table 1S: module=lightyellow & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the lightyellow module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M5968
exact_source: Table 1S: module=green & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the green module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M19520
exact_source: Table 1S: module=green & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the green module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M12517
exact_source: Table 1S: module=blue & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the blue module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M4397
exact_source: Table 1S: module=black & fold change < 0.667
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the black module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


systematic_name: M19133
exact_source: Table 1S: module=grey & fold change >= 1.5
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes from the grey module which are up-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).

description_full:
[cell repeats an earlier one in this file: 1667 characters]


description_brief: Up-regulated genes detecting gender effects in global expression profiling studies.
systematic_name: M17072
exact_source: Table 2, 5S
source_species_code: HS
GEO_id: GSE8762
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Highly quantitative biomarkers of neurodegenerative disease remain an important need in the urgent quest for disease-modifying therapies. For Huntington's disease (HD), a genetic test is available (trait marker), but necessary state markers are still in development. In this report, we describe a large battery of transcriptomic tests explored as state biomarker candidates. In an attempt to exploit the known neuroinflammatory and transcriptional perturbations of disease, we measured relevant mRNAs in peripheral blood cells. The performance of these potential markers was weak overall, with only one mRNA, immediate early response 3 (IER3), showing a modest but significant increase of 32% in HD samples compared with controls. No statistically significant differences were found for any other mRNAs tested, including a panel of 12 RNA biomarkers identified in a previous report [Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, et al. (2005) Proc Natl Acad Sci USA 102:11023-11028]. The present results may nonetheless inform the future design and testing of HD biomarker strategies.


systematic_name: M10084
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-rgulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 6h.

description_full:
  NUP98-HOXA9, the chimeric protein resulting from the t(7;11)(p15;p15) chromosomal translocation, is a prototype of several NUP98 fusions that occur in myelodysplastic syndromes and acute myeloid leukemia. We examined its effect on differentiation, proliferation, and gene expression in primary human CD34+ hematopoietic cells. Colony-forming cell (CFC) assays in semisolid medium combined with morphologic examination and flow cytometric immunophenotyping revealed that NUP98-HOXA9 increased the numbers of erythroid precursors and impaired both myeloid and erythroid differentiation. In continuous liquid culture, cells transduced with NUP98-HOXA9 exhibited a biphasic growth curve with initial growth inhibition followed by enhanced long-term proliferation, suggesting an increase in the numbers of primitive self-renewing cells. This was confirmed by a dramatic increase in the numbers of long-term culture-initiating cells, the most primitive hematopoietic cells detectable in vitro. To understand the molecular mechanisms underlying the effects of NUP98-HOXA9 on hematopoietic cell proliferation and differentiation, oligonucleotide microarray analysis was done at several time points over 16 days, starting at 6 hours posttransduction. The early growth suppression was preceded by up-regulation of IFNbeta1 and accompanied by marked up-regulation of IFN-induced genes, peaking at 3 days posttransduction. In contrast, oncogenes such as homeobox transcription factors, FLT3, KIT, and WT1 peaked at 8 days or beyond, coinciding with increased proliferation. In addition, several putative tumor suppressors and genes associated with hematopoietic differentiation were repressed at later time points. These findings provide a comprehensive picture of the changes in proliferation, differentiation, and global gene expression that underlie the leukemic transformation of human hematopoietic cells by NUP98-HOXA9.


systematic_name: M3210
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in CD34+ [GeneID=947] hematopoetic cells by expression of NUP98-HOXA9 fusion [GeneID=4928;3205] off a retroviral vector at 3 days after transduction.

description_full:
  NUP98-HOXA9, the chimeric protein resulting from the t(7;11)(p15;p15) chromosomal translocation, is a prototype of several NUP98 fusions that occur in myelodysplastic syndromes and acute myeloid leukemia. We examined its effect on differentiation, proliferation, and gene expression in primary human CD34+ hematopoietic cells. Colony-forming cell (CFC) assays in semisolid medium combined with morphologic examination and flow cytometric immunophenotyping revealed that NUP98-HOXA9 increased the numbers of erythroid precursors and impaired both myeloid and erythroid differentiation. In continuous liquid culture, cells transduced with NUP98-HOXA9 exhibited a biphasic growth curve with initial growth inhibition followed by enhanced long-term proliferation, suggesting an increase in the numbers of primitive self-renewing cells. This was confirmed by a dramatic increase in the numbers of long-term culture-initiating cells, the most primitive hematopoietic cells detectable in vitro. To understand the molecular mechanisms underlying the effects of NUP98-HOXA9 on hematopoietic cell proliferation and differentiation, oligonucleotide microarray analysis was done at several time points over 16 days, starting at 6 hours posttransduction. The early growth suppression was preceded by up-regulation of IFNbeta1 and accompanied by marked up-regulation of IFN-induced genes, peaking at 3 days posttransduction. In contrast, oncogenes such as homeobox transcription factors, FLT3, KIT, and WT1 peaked at 8 days or beyond, coinciding with increased proliferation. In addition, several putative tumor suppressors and genes associated with hematopoietic differentiation were repressed at later time points. These findings provide a comprehensive picture of the changes in proliferation, differentiation, and global gene expression that underlie the leukemic transformation of human hematopoietic cells by NUP98-HOXA9.


description_brief: Top genes higher expressed in short term mesothelioma survivors.
systematic_name: M540
exact_source: Table 5AS: short-term
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Most gene expression profiling studies of mesothelioma have been based on relatively small sample numbers, limiting their statistical power. We did Affymetrix U133A microarray analysis on 99 pleural mesotheliomas, in which multivariate analysis showed advanced-stage, sarcomatous histology and P16/CDKN2A homozygous deletion to be significant independent adverse prognostic factors. Comparison of the expression profiles of epithelioid versus sarcomatous mesotheliomas identified many genes significantly overexpressed among the former, including previously unrecognized ones, such as uroplakins and kallikrein 11, both confirmed by immunohistochemistry. Examination of the gene expression correlates of survival showed that more aggressive mesotheliomas expressed higher levels of Aurora kinases A and B and functionally related genes involved in mitosis and cell cycle control. Independent confirmation of the negative effect of Aurora kinase B was obtained by immunohistochemistry in a separate patient cohort. A role for Aurora kinases in the aggressive behavior of mesotheliomas is of potential clinical interest because of the recent development of small-molecule inhibitors. We then used our data to develop microarray-based predictors of 1 year survival; these achieved a maximal accuracy of 68% in cross-validation. However, this was inferior to prognostic prediction based on standard clinicopathologic variables and P16/CDNK2A status (accuracy, 73%), and adding the microarray model to the latter did not improve overall accuracy. Finally, we evaluated three recently published microarray-based outcome prediction models, but their accuracies ranged from 63% to 67%, consistently lower than reported. Gene expression profiling of mesotheliomas is an important discovery tool, but its power in clinical prognostication has been overestimated.


systematic_name: M14736
exact_source: Table 1: Relative ratio > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ALL (acute lymphoblastic leukemia) patients who developed t-ML (treatment related myeloid leukemia).

description_full:
  Using a target gene approach, only a few host genetic risk factors for treatment-related myeloid leukemia (t-ML) have been defined. Gene expression microarrays allow for a more genome-wide approach to assess possible genetic risk factors for t-ML. We assessed gene expression profiles (n=12 625 probe sets) in diagnostic acute lymphoblastic leukemic cells from 228 children treated on protocols that included leukemogenic agents such as etoposide, 13 of whom developed t-ML. Expression of 68 probes, corresponding to 63 genes, was significantly related to risk of t-ML. Hierarchical clustering of these probe sets clustered patients into three groups with 94, 122 and 12 patients, respectively; 12 of the 13 patients who went on to develop t-ML were overrepresented in the latter group (P<0.0001). A permutation test indicated a low likelihood that these probe sets and clusters were obtained by chance (P<0.001). Distinguishing genes included transcription-related oncogenes (v-Myb, Pax-5), cyclins (CCNG1, CCNG2 and CCND1) and histone HIST1H4C. Common transcription factor recognition elements among similarly up- or downregulated genes included several involved in hematopoietic differentiation or leukemogenesis (Maz, PU.1, ARNT). This approach has identified several genes whose expression distinguishes patients at risk of t-ML, and suggests targets for assessing germline predisposition to leukemogenesis.


systematic_name: M8981
exact_source: Table 1: Relative ratio < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in ALL (acute lymphoblastic leukemia) patients who developed t-ML (treatment related myeloid leukemia).

description_full:
  Using a target gene approach, only a few host genetic risk factors for treatment-related myeloid leukemia (t-ML) have been defined. Gene expression microarrays allow for a more genome-wide approach to assess possible genetic risk factors for t-ML. We assessed gene expression profiles (n=12 625 probe sets) in diagnostic acute lymphoblastic leukemic cells from 228 children treated on protocols that included leukemogenic agents such as etoposide, 13 of whom developed t-ML. Expression of 68 probes, corresponding to 63 genes, was significantly related to risk of t-ML. Hierarchical clustering of these probe sets clustered patients into three groups with 94, 122 and 12 patients, respectively; 12 of the 13 patients who went on to develop t-ML were overrepresented in the latter group (P<0.0001). A permutation test indicated a low likelihood that these probe sets and clusters were obtained by chance (P<0.001). Distinguishing genes included transcription-related oncogenes (v-Myb, Pax-5), cyclins (CCNG1, CCNG2 and CCND1) and histone HIST1H4C. Common transcription factor recognition elements among similarly up- or downregulated genes included several involved in hematopoietic differentiation or leukemogenesis (Maz, PU.1, ARNT). This approach has identified several genes whose expression distinguishes patients at risk of t-ML, and suggests targets for assessing germline predisposition to leukemogenesis.


systematic_name: M19930
exact_source: Table 1AS
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in B-CLL (B-cell chronic leukemia) samples expressing high levels of LPL [GeneID=4023] compared with those expressing low levels of the gene.

description_full:
  Lipoprotein lipase (LPL) is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL) related to immunoglobulin V(H) gene (IgV(H))mutational status. We determined gene expression profiles using Affymetrix U133A GeneChips in two groups of B-CLLs selected for either high ('LPL+', n=10) or low ('LPL-', n=10) LPL mRNA expression. Selected genes were verified by real-time PCR in an extended patient cohort (n=42). A total of 111 genes discriminated LPL+ from LPL- B-CLLs. Of these, the top three genes associated with time to first treatment were Septin10, DMD and Gravin (P</=0.01). The relationship of LPL+ and LPL- B-CLL gene expression signatures to 52 tissues was statistically analyzed. The LPL+ B-CLL expression signature, represented by 64 genes was significantly related to fat, muscle and PB dendritic cells (P<0.001). Exploration of microarray data to define functional alterations related to the biology of LPL+ CLL identified two functional modules, fatty acid degradation and MTA3 signaling, as being altered with higher statistical significance. Our data show that LPL+ B-CLL cells have not only acquired gene expression changes in fat and muscle-associated genes but also in functional pathways related to fatty acid degradation and signaling which may ultimately influence CLL biology and clinical outcome.


systematic_name: M14940
exact_source: Table 1BS
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in B-CLL (B-cell chronic leukemia) samples expressing high levels of LPL [GeneID=4023] compared with those expressing low levels of the gene.

description_full:
  Lipoprotein lipase (LPL) is a prognostic marker in B-cell chronic lymphocytic leukemia (B-CLL) related to immunoglobulin V(H) gene (IgV(H))mutational status. We determined gene expression profiles using Affymetrix U133A GeneChips in two groups of B-CLLs selected for either high ('LPL+', n=10) or low ('LPL-', n=10) LPL mRNA expression. Selected genes were verified by real-time PCR in an extended patient cohort (n=42). A total of 111 genes discriminated LPL+ from LPL- B-CLLs. Of these, the top three genes associated with time to first treatment were Septin10, DMD and Gravin (P</=0.01). The relationship of LPL+ and LPL- B-CLL gene expression signatures to 52 tissues was statistically analyzed. The LPL+ B-CLL expression signature, represented by 64 genes was significantly related to fat, muscle and PB dendritic cells (P<0.001). Exploration of microarray data to define functional alterations related to the biology of LPL+ CLL identified two functional modules, fatty acid degradation and MTA3 signaling, as being altered with higher statistical significance. Our data show that LPL+ B-CLL cells have not only acquired gene expression changes in fat and muscle-associated genes but also in functional pathways related to fatty acid degradation and signaling which may ultimately influence CLL biology and clinical outcome.


systematic_name: M14698
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in the common lymphoid progenitor (CLP, defined as CD34+CD38-CD7+ [GeneID=947;952;924]) compared to a multipotent cord blood cell (defined as CD34+CD38+CD7-).

description_full:
  Hematopoietic stem cells in the bone marrow (BM) give rise to all blood cells. According to the classic model of hematopoiesis, the differentiation paths leading to the myeloid and lymphoid lineages segregate early. A candidate 'common lymphoid progenitor' (CLP) has been isolated from CD34(+)CD38(-) human cord blood cells based on CD7 expression. Here, we confirm the B- and NK-differentiation potential of CD34(+)CD38(-)CD7(+) cells and show in addition that this population has strong capacity to differentiate into T cells. As CD34(+)CD38(-)CD7(+) cells are virtually devoid of myeloid differentiation potential, these cells represent true CLPs. To unravel the molecular mechanisms underlying lymphoid commitment, we performed genome-wide gene expression profiling on sorted CD34(+)CD38(-)CD7(+) and CD34(+)CD38(-)CD7(-) cells. Interestingly, lymphoid-affiliated genes were mainly upregulated in the CD7(+) population, while myeloid-specific genes were downregulated. This supports the hypothesis that lineage commitment is accompanied by the shutdown of inappropriate gene expression and the upregulation of lineage-specific genes. In addition, we identified several highly expressed genes that have not been described in hematopoiesis before.


systematic_name: M7435
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the common lymphoid progenitor (CLP, defined as CD34+CD38-CD7+ [GeneID=947;952;924]) compared to a multipotent cord blood cell (defined as CD34+CD38+CD7-).

description_full:
  Hematopoietic stem cells in the bone marrow (BM) give rise to all blood cells. According to the classic model of hematopoiesis, the differentiation paths leading to the myeloid and lymphoid lineages segregate early. A candidate 'common lymphoid progenitor' (CLP) has been isolated from CD34(+)CD38(-) human cord blood cells based on CD7 expression. Here, we confirm the B- and NK-differentiation potential of CD34(+)CD38(-)CD7(+) cells and show in addition that this population has strong capacity to differentiate into T cells. As CD34(+)CD38(-)CD7(+) cells are virtually devoid of myeloid differentiation potential, these cells represent true CLPs. To unravel the molecular mechanisms underlying lymphoid commitment, we performed genome-wide gene expression profiling on sorted CD34(+)CD38(-)CD7(+) and CD34(+)CD38(-)CD7(-) cells. Interestingly, lymphoid-affiliated genes were mainly upregulated in the CD7(+) population, while myeloid-specific genes were downregulated. This supports the hypothesis that lineage commitment is accompanied by the shutdown of inappropriate gene expression and the upregulation of lineage-specific genes. In addition, we identified several highly expressed genes that have not been described in hematopoiesis before.


description_brief: Genes up-regulated in CD38+ [GeneID=952] CLL (chronic lymphocytic leukemia) cells.
systematic_name: M3340
exact_source: Table 1AS
source_species_code: HS
GEO_id: GSE6321
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  CD38 expression is an important prognostic marker in chronic lymphocytic leukemia (CLL) with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38(+) and CD38(-) chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38(+) and CD38(-) CLL cells derived from the same patient were shown to be monoclonal by V(H) gene sequencing but despite this, CD38(+) CLL cells possessed a distinct gene expression profile when compared with their CD38(-) sub-clones. Importantly, CD38(+) CLL cells relatively over expressed vascular endothelial growth factor (VEGF) and appeared to preferentially utilize an internal autocrine VEGF survival loop. Elevated VEGF expression was associated with increased expression of the anti-apoptotic protein Mcl-1. Inhibition of VEGF receptor signaling also resulted in a reduction in cell viability. In contrast, exogenous VEGF caused a significant increase in CD38(-) CLL cell viability and a marked induction of Mcl-1; both effects were less obvious in CD38(+) CLL cells. Taken together, our data provide a biological rationale for the poor prognosis of CD38(+) CLL and indicate that both VEGF and Mcl-1 may prove to be useful therapeutic targets.


systematic_name: M7705
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in WE17/10 cells (CD4+ [GeneID=920] T lymphocytes) infected by HTLV1 (and thus displaying low CD7 [GeneID=924]) compared to the uninfected (i.e., CD7+) cells.

description_full:
  Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4(+) T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL.


systematic_name: M9815
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in WE17/10 cells (CD4+ [GeneID=920] T lymphocytes) infected by HTLV1 (and thus displaying low CD7 [GeneID=924]) compared to the uninfected (i.e., CD7+) cells.

description_full:
  Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4(+) T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL.


systematic_name: M12784
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in ALL (acute lymphoblastic leukemia) blasts after 1 week of treatment with glucocorticoids.

description_full:
  In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. In the present study, we address molecular and cell biologic features of blasts persisting after 1 week of induction glucocorticoid therapy. Genome-wide gene expression analysis of leukemic samples from precursor B-cell ALL patients (n=18) identified a set of genes differentially expressed in blasts at diagnosis day 0 (d0) and persisting on day 8 (d8). Expression changes indicate a shift towards mature B cells, inhibition of cell cycling and increased expression of adhesion (CD11b/ITGAM) and cytokine (CD119/IFNGR1) receptors. A direct comparison with normal B cells, which are largely therapy resistant, confirmed the differentiation shift at the mRNA (n=10) and protein (n=109) levels. Flow cytometric analysis in independent cohorts of patients confirmed both a decreased proliferative activity (n=13) and the upregulation of CD11b and CD119 (n=29) in d8 blasts. The differentiation shift and low proliferative activity in d8 blasts may account for the persistence of blasts during therapy and affect their sensitivity to further therapeutic treatment. CD11b and CD119 are potential specific markers for d8 blast persistence and detection of minimal residual disease, which warrant further investigation.


systematic_name: M19170
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'NPM1-mutated signature 1': genes up-regulated in pediatric AML (acute myeloid leukemia) samples with mutated NPM1 [GeneID=4869] compared to all AML cases with the intact gene.

description_full:
  Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.


systematic_name: M19629
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'NPM1-mutated signature 1': genes down-regulated in pediatric AML (acute myeloid leukemia) samples with mutated NPM1 [GeneID=4869] compared to all AML cases with the intact gene.

description_full:
  Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.


systematic_name: M6590
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'NPM1-mutated signature 2': genes up-regulated in pediatric AML (acute myeloid leukemia) samples with mutated NPM1 [GeneID=4869] compared to the AML cases with the intact gene and without recurring cytogenetic anomalities or M7 phenotype.

description_full:
  Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.


systematic_name: M8315
exact_source: Table 3S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'NPM1-mutated signature 2': genes down-regulated in pediatric AML (acute myeloid leukemia) samples with mutated NPM1 [GeneID=4869] compared to the AML cases with the intact gene and without recurring cytogenetic anomalities or M7 phenotype.

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M17856
exact_source: Table 5S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'MLL signature 1': genes up-regulated in pediatric AML (acute myeloid leukemia) with rearranged MLL [GeneID=4297] compared to all AML cases with the intact gene.

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M18841
exact_source: Table 5S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'MLL signature 1': genes down-regulated in pediatric AML (acute myeloid leukemia) with rearranged MLL [GeneID=4297] compared to all AML cases with the intact gene.

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M3053
exact_source: Table 6S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'MLL signature 2': genes up-regulated in pediatric AML (acute myeloid leukemia) with rearranged MLL [GeneID=4297] compared to the AML cases with intact MLL and NPM1 [GeneID=4869].

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M16867
exact_source: Table 6S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'MLL signature 2': genes down-regulated in pediatric AML (acute myeloid leukemia) with rearranged MLL [GeneID=4297] compared to the AML cases with intact MLL and NPM1 [GeneID=4869].

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M10277
exact_source: Table 7S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'NPM1 signature 3': genes up-regulated in pediatric AML (acute myeloid leukemia) with mutated NPM1 [GeneID=4869] compared to the AML cases with intact NPM1 and MLL [GeneID=4297].

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M15047
exact_source: Table 7S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  The 'NPM1 signature 3': genes down-regulated in pediatric AML (acute myeloid leukemia) with mutated NPM1 [GeneID=4869] compared to the AML cases with intact NPM1 and MLL [GeneID=4297].

description_full:
[cell repeats an earlier one in this file: 1293 characters]


systematic_name: M5395
exact_source: Table 1
source_species_code: HS
GEO_id: E-MEXP-583
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by RUNX1-RUNX1T1 [GeneID=861;862] fusion protein in normal hematopoietic progenitors; their expression was sustained in subsequently developing granulocytes.

description_full:
  The t(8;21)(q22;q22) occurs frequently in acute myelogenous leukaemia and gives rise to the transcription factor fusion protein, RUNX1-RUNX1T1 (also known as AML1-ETO). To identify the genes dysregulated by the aberrant transcriptional activity of RUNX1-RUNX1T1, we used microarrays to determine the effect of this mutation on gene expression in human progenitor cells and during subsequent development. Gene signatures of these developmental subsets were very dissimilar indicating that effects of RUNX1-RUNX1T1 are highly context dependent. We focused on gene changes associated with the granulocytic lineage and identified a clinically relevant subset of these by comparison with 235 leukaemia patient transcriptional signatures. We confirmed the overexpression of a number of significant genes (Sox4, IL-17BR, CD200 and gamma-catenin). Further, we show that overexpression of CD200 and gamma-catenin is also associated with the inv(16) abnormality which like RUNX1-RUNX1T1 disrupts core binding factor activity. We investigated the functional significance of CD200 and gamma-catenin overexpression in normal human progenitor cells. The effect of IL17 on growth was also assessed. Individually, none of these changes were sufficient to recapitulate the effects of RUNX1-RUNX1T1 on normal development. These data provide the most comprehensive and pertinent assessment of the effect of RUNX1-RUNX1T1 on gene expression and demonstrate the highly context-dependent effects of this fusion gene.


systematic_name: M6161
exact_source: Table 1
source_species_code: HS
GEO_id: E-MEXP-583
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by RUNX1-RUNX1T1 [GeneID=861;862] fusion protein in normal hematopoietic progenitors; their expression was sustained in subsequently developing granulocytes.

description_full:
  The t(8;21)(q22;q22) occurs frequently in acute myelogenous leukaemia and gives rise to the transcription factor fusion protein, RUNX1-RUNX1T1 (also known as AML1-ETO). To identify the genes dysregulated by the aberrant transcriptional activity of RUNX1-RUNX1T1, we used microarrays to determine the effect of this mutation on gene expression in human progenitor cells and during subsequent development. Gene signatures of these developmental subsets were very dissimilar indicating that effects of RUNX1-RUNX1T1 are highly context dependent. We focused on gene changes associated with the granulocytic lineage and identified a clinically relevant subset of these by comparison with 235 leukaemia patient transcriptional signatures. We confirmed the overexpression of a number of significant genes (Sox4, IL-17BR, CD200 and gamma-catenin). Further, we show that overexpression of CD200 and gamma-catenin is also associated with the inv(16) abnormality which like RUNX1-RUNX1T1 disrupts core binding factor activity. We investigated the functional significance of CD200 and gamma-catenin overexpression in normal human progenitor cells. The effect of IL17 on growth was also assessed. Individually, none of these changes were sufficient to recapitulate the effects of RUNX1-RUNX1T1 on normal development. These data provide the most comprehensive and pertinent assessment of the effect of RUNX1-RUNX1T1 on gene expression and demonstrate the highly context-dependent effects of this fusion gene.


systematic_name: M7176
exact_source: Table 4S
source_species_code: HS
GEO_id: E-MEXP-583
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by RUNX1-RUNX1T1 [GeneID=861;862] fusion protein in normal hematopoietic progenitors; their expression was sustained in subsequently developing monocytes.

description_full:
[cell repeats an earlier one in this file: 1494 characters]


systematic_name: M4223
exact_source: Table 4S
source_species_code: HS
GEO_id: E-MEXP-583
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by RUNX1-RUNX1T1 [GeneID=861;862] fusion protein in normal hematopoietic progenitors; their expression was sustained in subsequently developing monocytes.

description_full:
[cell repeats an earlier one in this file: 1494 characters]


systematic_name: M12085
exact_source: Table 5S
source_species_code: HS
GEO_id: E-MEXP-583
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated by RUNX1-RUNX1T1 [GeneID=861;862] fusion protein in normal hematopoietic progenitors; their expression was sustained in subsequently developing erythroid lineage.

description_full:
[cell repeats an earlier one in this file: 1494 characters]


description_brief: Genes up-regulated in unstable ateroslerotic plaques compared to the stable ones.
systematic_name: M9936
exact_source: Table 4S: Fold change < 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  OBJECTIVE: Comparison of gene expression in stable versus unstable atherosclerotic plaque may be confounded by interpatient variability. The aim of this study was to identify differences in gene expression between stable and unstable segments of plaque obtained from the same patient. METHODS AND RESULTS: Human carotid endarterectomy specimens were segmented and macroscopically classified using a morphological classification system. Two analytical methods, an intraplaque and an interplaque analysis, revealed 170 and 1916 differentially expressed genes, respectively using Affymetrix gene chip analysis. A total of 115 genes were identified from both analyses. The differential expression of 27 genes was also confirmed using quantitative-polymerase chain reaction on a larger panel of samples. Eighteen of these genes have not been associated previously with plaque instability, including the metalloproteinase, ADAMDEC1 (approximately 37-fold), retinoic acid receptor responder-1 (approximately 5-fold), and cysteine protease legumain (approximately 3-fold). Matrix metalloproteinase-9 (MMP-9), cathepsin B, and a novel gene, legumain, a potential activator of MMPs and cathepsins, were also confirmed at the protein level. CONCLUSIONS: The differential expression of 18 genes not previously associated with plaque rupture has been confirmed in stable and unstable regions of the same atherosclerotic plaque. These genes may represent novel targets for the treatment of unstable plaque or useful diagnostic markers of plaque instability.


systematic_name: M11090
exact_source: Table 3S: Ind. = Up
source_species_code: HS
GEO_id: GSE4292
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MDA-MB-231 cells (breast cancer) after knockdown of PTHLH [GeneID=5744] by RNAi.

description_full:
  The effect of endogenous parathyroid hormone-related protein (PTHrP) on gene expression in breast cancer cells was studied. We suppressed PTHrP expression in MDA-MB-231 cells by RNA interference and analyzed changes in gene expression by microarray analysis. More than 200 genes showed altered expression in response to a PTHrP-specific small interfering (si) RNA (siPTHrP). Cell cycle-regulating gene CDC2 and genes (CDC25B and Tome-1) that control CDC2 activity showed increased expression in the presence of siPTHrP. CDC2 activity was also found to be higher in siPTHrP-treated cells. Studies with PTHrP peptides 1-34 and 67-86, forskolin, and a PTH1 receptor (PTH1R)-specific siRNA showed that PTHrP regulates CDC2 and CDC25B, at least in part, via PTH1R in a cAMP-independent manner. Other siPTHrP-responsive genes included integrin alpha6 (ITGA6), KISS-1, and PAI-1. When combined, siRNAs against ITGA6, PAI-1, and KISS-1 could mimic the negative effect of siPTHrP on migration, whereas siKISS-1 and siPTHrP similarly reduced the proliferative activity of the cells. Comparative expression analyses with 50 primary breast carcinomas revealed that the RNA level of ITGA6 correlates with that of PTHrP, and higher CDC2 and CDC25B values are found at low PTHrP expression. Our data suggest that PTHrP has a profound effect on gene expression in breast cancer cells and, as a consequence, contributes to the regulation of important cellular activities, such as migration and proliferation.


systematic_name: M18667
exact_source: Table 3S: Ind. = Down
source_species_code: HS
GEO_id: GSE4292
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MDA-MB-231 cells (breast cancer) after knockdown of PTHLH [GeneID=5744] by RNAi.

description_full:
  The effect of endogenous parathyroid hormone-related protein (PTHrP) on gene expression in breast cancer cells was studied. We suppressed PTHrP expression in MDA-MB-231 cells by RNA interference and analyzed changes in gene expression by microarray analysis. More than 200 genes showed altered expression in response to a PTHrP-specific small interfering (si) RNA (siPTHrP). Cell cycle-regulating gene CDC2 and genes (CDC25B and Tome-1) that control CDC2 activity showed increased expression in the presence of siPTHrP. CDC2 activity was also found to be higher in siPTHrP-treated cells. Studies with PTHrP peptides 1-34 and 67-86, forskolin, and a PTH1 receptor (PTH1R)-specific siRNA showed that PTHrP regulates CDC2 and CDC25B, at least in part, via PTH1R in a cAMP-independent manner. Other siPTHrP-responsive genes included integrin alpha6 (ITGA6), KISS-1, and PAI-1. When combined, siRNAs against ITGA6, PAI-1, and KISS-1 could mimic the negative effect of siPTHrP on migration, whereas siKISS-1 and siPTHrP similarly reduced the proliferative activity of the cells. Comparative expression analyses with 50 primary breast carcinomas revealed that the RNA level of ITGA6 correlates with that of PTHrP, and higher CDC2 and CDC25B values are found at low PTHrP expression. Our data suggest that PTHrP has a profound effect on gene expression in breast cancer cells and, as a consequence, contributes to the regulation of important cellular activities, such as migration and proliferation.


description_brief: Genes up-regulated in HeLa cells after knockdown of MED1 [GeneID=5469] by RNAi.
systematic_name: M3909
exact_source: Table S1: Pvalue <= 0.001 & Fold change > 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  The TRAP/Mediator coactivator complex serves as a functional interface between DNA-bound transactivators and the RNA polymerase II-associated basal transcription apparatus. TRAP220/MED1 is a variably associated subunit of the complex that plays a specialized role in selectively targeting TRAP/Mediator to specific genes. Ablation of the Trap220/Med1 gene in mice impairs embryonic cell growth, yet the underlying mechanism is unknown. In this report, we identified distinct cell growth regulatory genes whose expression is affected by the loss of TRAP220/MED1 by RNA interference. Among the down-regulated genes revealed by cDNA microarray analyses, we identified Aurora-A, a centrosome kinase that plays a critical role in regulating M phase events and is frequently amplified in several types of cancer. In general, we found that TRAP220/MED1 expression is required for high basal levels of Aurora-A gene expression and that ectopic overexpression of TRAP220/MED1 coactivates transcription from the Aurora-A gene promoter. Furthermore, chromatin immunoprecipitation assays show that TRAP220/MED1-containing TRAP/Mediator complexes directly bind to the Aurora-A promoter in vivo. Finally, we present evidence suggesting that TRAP/Mediator is recruited to the Aurora-A gene via direct interactions between TRAP220/MED1 and the Ets-related transcription factor GABP. Taken together, these findings suggest that TRAP220/MED1 plays a novel coregulatory role in facilitating the recruitment of TRAP/Mediator to specific target genes involved in growth and cell cycle progression.


systematic_name: M6753
exact_source: Table 7AS: fold change > 2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in P493-6 cells (B lymphocyte, Burkitt's lymphoma model) upon knockdown of TFRC [GeneID=7037] by RNAi.

description_full:
  Overexpression of transferrin receptor 1 (TFRC1), a major mediator of iron uptake in mammalian cells, is a common feature of human malignancies. Therapeutic strategies designed to interfere with tumor iron metabolism have targeted TFRC1. The c-Myc oncogenic transcription factor stimulates proliferation and growth by activating thousands of target genes. Here we demonstrate that TFRC1 is a critical downstream target of c-Myc. Using in vitro and in vivo models of B-cell lymphoma, we show that TFRC1 expression is activated by c-Myc. Chromatin immunoprecipitation experiments reveal that c-Myc directly binds a conserved region of TFRC1. In light of these findings, we sought to determine whether TFRC1 is required for c-Myc-mediated cellular proliferation and cell size control. TFRC1 inhibition decreases cellular proliferation and results in G1 arrest without affecting cell size. Consistent with these findings, expression profiling reveals that TFRC1 depletion alters expression of genes that regulate the cell cycle. Furthermore, enforced TFRC1 expression confers a growth advantage to cells and significantly enhances the rate of c-Myc-mediated tumor formation in vivo. These findings provide a molecular basis for increased TFRC1 expression in human tumors, illuminate the role of TFRC1 in the c-Myc target gene network, and support strategies that target TFRC1 for cancer therapy.


systematic_name: M13183
exact_source: Table 7CS
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in P493-6 cells (B lymphocyte, Burkitt's lymphoma model) by MYC [GeneID=4609] and up-regulated by RNAi knockdown of TFRC [GeneID=7037].

description_full:
  Overexpression of transferrin receptor 1 (TFRC1), a major mediator of iron uptake in mammalian cells, is a common feature of human malignancies. Therapeutic strategies designed to interfere with tumor iron metabolism have targeted TFRC1. The c-Myc oncogenic transcription factor stimulates proliferation and growth by activating thousands of target genes. Here we demonstrate that TFRC1 is a critical downstream target of c-Myc. Using in vitro and in vivo models of B-cell lymphoma, we show that TFRC1 expression is activated by c-Myc. Chromatin immunoprecipitation experiments reveal that c-Myc directly binds a conserved region of TFRC1. In light of these findings, we sought to determine whether TFRC1 is required for c-Myc-mediated cellular proliferation and cell size control. TFRC1 inhibition decreases cellular proliferation and results in G1 arrest without affecting cell size. Consistent with these findings, expression profiling reveals that TFRC1 depletion alters expression of genes that regulate the cell cycle. Furthermore, enforced TFRC1 expression confers a growth advantage to cells and significantly enhances the rate of c-Myc-mediated tumor formation in vivo. These findings provide a molecular basis for increased TFRC1 expression in human tumors, illuminate the role of TFRC1 in the c-Myc target gene network, and support strategies that target TFRC1 for cancer therapy.


systematic_name: M10276
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in the neural crest stem cells (NCS), defined as p75+/HNK1+ [GeneID=4804;27087].

description_full:
  Vertebrate neural crest development depends on pluripotent, migratory precursor cells. Although avian and murine neural crest stem (NCS) cells have been identified, the isolation of human NCS cells has remained elusive. Here we report the derivation of NCS cells from human embryonic stem cells at the neural rosette stage. We show that NCS cells plated at clonal density give rise to multiple neural crest lineages. The human NCS cells can be propagated in vitro and directed toward peripheral nervous system lineages (peripheral neurons, Schwann cells) and mesenchymal lineages (smooth muscle, adipogenic, osteogenic and chondrogenic cells). Transplantation of human NCS cells into the developing chick embryo and adult mouse hosts demonstrates survival, migration and differentiation compatible with neural crest identity. The availability of unlimited numbers of human NCS cells offers new opportunities for studies of neural crest development and for efforts to model and treat neural crest-related disorders.


description_brief: Up-regulated genes constituting the molecular signature of Burkitt 's lymphoma.
systematic_name: M3134
exact_source: Table 5.3.1S
source_species_code: HS
GEO_id: GSE4475
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. METHODS: We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. RESULTS: We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. CONCLUSIONS: Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.


systematic_name: M6740
exact_source: Table S3
source_species_code: HS
GEO_id: GSE8671
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  A selection of genes whose expression displayed significant positive correlation with size of colorectal adenoma.

description_full:
  Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the beta-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation.


systematic_name: M11303
exact_source: Table S3
source_species_code: HS
GEO_id: GSE8671
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  A selection of genes whose expression displayed significant negative correlation with size of colorectal adenoma.

description_full:
  Colorectal cancers are believed to arise predominantly from adenomas. Although these precancerous lesions have been subjected to extensive clinical, pathologic, and molecular analyses, little is currently known about the global gene expression changes accompanying their formation. To characterize the molecular processes underlying the transformation of normal colonic epithelium, we compared the transcriptomes of 32 prospectively collected adenomas with those of normal mucosa from the same individuals. Important differences emerged not only between the expression profiles of normal and adenomatous tissues but also between those of small and large adenomas. A key feature of the transformation process was the remodeling of the Wnt pathway reflected in patent overexpression and underexpression of 78 known components of this signaling cascade. The expression of 19 Wnt targets was closely correlated with clear up-regulation of KIAA1199, whose function is currently unknown. In normal mucosa, KIAA1199 expression was confined to cells in the lower portion of intestinal crypts, where Wnt signaling is physiologically active, but it was markedly increased in all adenomas, where it was expressed in most of the epithelial cells, and in colon cancer cell lines, it was markedly reduced by inactivation of the beta-catenin/T-cell factor(s) transcription complex, the pivotal mediator of Wnt signaling. Our transcriptomic profiles of normal colonic mucosa and colorectal adenomas shed new light on the early stages of colorectal tumorigenesis and identified KIAA1199 as a novel target of the Wnt signaling pathway and a putative marker of colorectal adenomatous transformation.


systematic_name: M1142
exact_source: Table S2
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in HB2 cells (mammary epithelium) upon expression of KDM5B [GeneID=10765] off an adenoviral vector.

description_full:
  The PLU-1/JARID1B nuclear protein, which is upregulated in breast cancers, belongs to the ARID family of DNA binding proteins and has strong transcriptional repression activity. To identify the target genes regulated by PLU-1/JARID1B, we overexpressed or silenced the human PLU-1/JARID1B gene in human mammary epithelial cells by using adenovirus and RNA interference systems, respectively, and then applied microarray analysis to identify candidate genes. A total of 100 genes showed inversely correlated differential expression in the two systems. Most of the candidate genes were downregulated by the overexpression of PLU-1/JARID1B, including the MT genes, the tumor suppressor gene BRCA1, and genes involved in the regulation of the M phase of the mitotic cell cycle. Chromatin immunoprecipitation assays confirmed that the metallothionein 1H (MT1H), -1F, and -1X genes are direct transcriptional targets of PLU-1/JARID1B in vivo. Furthermore, the level of trimethyl H3K4 of the MT1H promoter was increased following silencing of PLU-1/JARID1B. Both the PLU-1/JARID1B protein and the ARID domain selectively bound CG-rich DNA. The GCACA/C motif, which is abundant in metallothionein promoters, was identified as a consensus binding sequence of the PLU-1/JARID1B ARID domain. As expected from the microarray data, cells overexpressing PLU-1/JARID1B have an impaired G(2)/M checkpoint. Our study provides insight into the molecular function of the breast cancer-associated transcriptional repressor PLU-1/JARID1B.


description_brief: Genes down-regulated in MCF7 cells (breast cancer) after stimulation with NRG1 [GeneID=3084].
systematic_name: M17600
exact_source: Table 1S: HRG fold change -
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  ErbB receptor ligands, epidermal growth factor (EGF) and heregulin (HRG), induce dose-dependent transient and sustained intracellular signaling, proliferation, and differentiation of MCF-7 breast cancer cells, respectively. In an effort to delineate the ligand-specific cell determination mechanism, we investigated time course gene expressions induced by EGF and HRG that induce distinct cellular phenotypes in MCF-7 cells. To analyze independently the effects of ligand dosage and time for gene expression, we developed a statistical method for estimating the two effects. Our results indicated that signal transduction pathways convey quantitative properties of the dose-dependent activation of ErbB receptor to early transcription. The results also implied that moderate changes in the expression levels of a number of genes, not the predominant regulation of a few specific genes, might cooperatively work at the early stage of the transcription for determining cell fate. However, the EGF- and HRG-induced distinct signal durations resulted in the ligand-oriented biphasic induction of proteins after 20 min. The selected gene list and HRG-induced prolonged signaling suggested that transcriptional feedback to the intracellular signaling results in a graded to biphasic response in the cell determination process and that each ErbB receptor is inextricably responsible for the control of amplitude and duration of cellular biochemical reactions.


description_brief: Genes down-regulated in MCF7 cells (breast cancer) under hypoxia conditions.
systematic_name: M10175
exact_source: Tables 4S: Hypoxia fold change < 0
source_species_code: HS
GEO_id: GSE3188
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Studies of gene regulation by oxygen have revealed novel signal pathways that regulate the hypoxia-inducible factor (HIF) transcriptional system through post-translational hydroxylation of specific prolyl and asparaginyl residues in HIF-alpha subunits. These oxygen-sensitive modifications are catalyzed by members of the 2-oxoglutarate (2-OG) dioxygenase family (PHD1, PHD2, PHD3, and FIH-1), raising an important question regarding the extent of involvement of these and other enzymes of the same family in directing the global changes in gene expression that are induced by hypoxia. To address this, we compared patterns of gene expression induced by hypoxia and by a nonspecific 2-OG-dependent dioxygenase inhibitor, dimethyloxalylglycine (DMOG), among a set of 22,000 transcripts, by microarray analysis of MCF7 cells. By using short interfering RNA-based suppression of HIF-alpha subunits, we also compared responses that were dependent on, or independent of, the HIF system. Results revealed striking concordance between patterns of gene expression induced by hypoxia and by DMOG, indicating the central involvement of 2-OG-dependent dioxygenases in oxygen-regulated gene expression. Many of these responses were suppressed by short interfering RNAs directed against HIF-1alpha and HIF-2alpha, with HIF-1alpha suppression manifesting substantially greater effects than HIF-2alpha suppression, supporting the importance of HIF pathways. Nevertheless, the definition of genes regulated by both hypoxia and DMOG, but not HIF, distinguished other pathways most likely involving the action of 2-OG-dependent dioxygenases on non-HIF substrates.


systematic_name: M7030
exact_source: Tables 3S, 4S: DMOG fold change < 0 & q-val < 0.01
source_species_code: HS
GEO_id: GSE3188
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in MCF7 cells (breast cancer) treated with hypoxia mimetic DMOG [PubChem=3080614].

description_full:
  Studies of gene regulation by oxygen have revealed novel signal pathways that regulate the hypoxia-inducible factor (HIF) transcriptional system through post-translational hydroxylation of specific prolyl and asparaginyl residues in HIF-alpha subunits. These oxygen-sensitive modifications are catalyzed by members of the 2-oxoglutarate (2-OG) dioxygenase family (PHD1, PHD2, PHD3, and FIH-1), raising an important question regarding the extent of involvement of these and other enzymes of the same family in directing the global changes in gene expression that are induced by hypoxia. To address this, we compared patterns of gene expression induced by hypoxia and by a nonspecific 2-OG-dependent dioxygenase inhibitor, dimethyloxalylglycine (DMOG), among a set of 22,000 transcripts, by microarray analysis of MCF7 cells. By using short interfering RNA-based suppression of HIF-alpha subunits, we also compared responses that were dependent on, or independent of, the HIF system. Results revealed striking concordance between patterns of gene expression induced by hypoxia and by DMOG, indicating the central involvement of 2-OG-dependent dioxygenases in oxygen-regulated gene expression. Many of these responses were suppressed by short interfering RNAs directed against HIF-1alpha and HIF-2alpha, with HIF-1alpha suppression manifesting substantially greater effects than HIF-2alpha suppression, supporting the importance of HIF pathways. Nevertheless, the definition of genes regulated by both hypoxia and DMOG, but not HIF, distinguished other pathways most likely involving the action of 2-OG-dependent dioxygenases on non-HIF substrates.


systematic_name: M7062
exact_source: Tables 3S, 4S: HIF12si fold change > 0 & q-value < 0.01
source_species_code: HS
GEO_id: GSE3188
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MCF7 cells (breast cancer) after knockdown of both HIF1A and HIF2A [GeneID=3091;2034] by RNAi.

description_full:
[cell repeats an earlier one in this file: 1645 characters]


systematic_name: M15107
exact_source: Table 2S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in CD133+ [GeneID=8842] cells (hematopoietic stem cells, HSC) compared to the CD133- cells.

description_full:
  Human cord blood (CB)-derived CD133+ cells carry characteristics of primitive hematopoietic cells and proffer an alternative for CD34+ cells in hematopoietic stem cell (HSC) transplantation. To characterize the CD133+ cell population on a genetic level, a global expression analysis of CD133+ cells was performed using oligonucleotide microarrays. CD133+ cells were purified from four fresh CB units by immunomagnetic selection. All four CD133+ samples showed significant similarity in their gene expression pattern, whereas they differed clearly from the CD133- control samples. In all, 690 transcripts were differentially expressed between CD133+ and CD133- cells. Of these, 393 were increased and 297 were decreased in CD133+ cells. The highest overexpression was noted in genes associated with metabolism, cellular physiological processes, cell communication, and development. A set of 257 transcripts expressed solely in the CD133+ cell population was identified. Colony-forming unit (CFU) assay was used to detect the clonal progeny of precursors present in the studied cell populations. The results demonstrate that CD133+ cells express primitive markers and possess clonogenic progenitor capacity. This study provides a gene expression profile for human CD133+ cells. It presents a set of genes that may be used to unravel the properties of the CD133+ cell population, assumed to be highly enriched in HSCs.


description_brief: Genes up-regulated in FSHD (facioscapulohumeral muscular dystrophy) mesoangioblasts.
systematic_name: M5409
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Facioscapulohumeral muscular dystrophy (FSHD) is the third most frequent inherited muscle disease. Because in FSHD patients the coexistence of affected and unaffected muscles is common, myoblasts expanded from unaffected FSHD muscles have been proposed as suitable tools for autologous cell transplantation. Mesoangioblasts are a new class of adult stem cells of mesodermal origin, potentially useful for the treatment of primitive myopathies of different etiology. Here, we report the isolation and characterization of mesoangioblasts from FSHD muscle biopsies and describe morphology, proliferation, and differentiation abilities of both mesoangioblasts and myoblasts derived from various affected and unaffected muscles of nine representative FSHD patients. We demonstrate that mesoangioblasts can be efficiently isolated from FSHD muscle biopsies and expanded to an amount of cells necessary to transplant into an adult patient. Proliferating mesoangioblasts from all muscles examined did not differ from controls in terms of morphology, phenotype, proliferation rate, or clonogenicity. However, their differentiation ability into skeletal muscle was variably impaired, and this defect correlated with the overall disease severity and the degree of histopathologic abnormalities of the muscle of origin. A remarkable differentiation defect was observed in mesoangioblasts from all mildly to severely affected FSHD muscles, whereas mesoangioblasts from morphologically normal muscles showed no myogenic differentiation block. Our study could open the way to cell therapy for FSHD patients to limit muscle damage in vivo through the use of autologous mesoangioblasts capable of reaching damaged muscles and engrafting into them, without requiring immune suppression or genetic correction in vitro. Disclosure of potential conflicts of interest is found at the end of this article.


systematic_name: M629
exact_source: Table 2S: Ratio CD/CG > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in quiescent (G0) vs dividing (M) CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloid leukemia) patients.

description_full:
  Quiescent and dividing hemopoietic stem cells (HSC) display marked differences in their ability to move between the peripheral circulation and the bone marrow. Specifically, long-term engraftment potential predominantly resides in the quiescent HSC subfraction, and G-CSF mobilization results in the preferential accumulation of quiescent HSC in the periphery. In contrast, stem cells from chronic myeloid leukemia (CML) patients display a constitutive presence in the circulation. To understand the molecular basis for this, we have used microarray technology to analyze the transcriptional differences between dividing and quiescent, normal, and CML-derived CD34+ cells. Our data show a remarkable transcriptional similarity between normal and CML dividing cells, suggesting that the effects of BCR-ABL on the CD34+ cell transcriptome are more limited than previously thought. In addition, we show that quiescent CML cells are more similar to their dividing counterparts than quiescent normal cells are to theirs. We also show these transcriptional differences to be reflected in the altered proliferative activity of normal and CML CD34+ cells. Of the most interest is that the major class of genes that is more abundant in the quiescent cells compared with the dividing cells encodes members of the chemokine family. We propose a role for chemokines expressed by quiescent HSC in the orchestration of CD34+ cell mobilization. Disclosure of potential conflicts of interest is found at the end of this article.


systematic_name: M11636
exact_source: Table 3S: Ratio NG/CG > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in quiescent (G0) CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloid leukemia) patients compared to the quiescent cells from normal donors.

description_full:
  Quiescent and dividing hemopoietic stem cells (HSC) display marked differences in their ability to move between the peripheral circulation and the bone marrow. Specifically, long-term engraftment potential predominantly resides in the quiescent HSC subfraction, and G-CSF mobilization results in the preferential accumulation of quiescent HSC in the periphery. In contrast, stem cells from chronic myeloid leukemia (CML) patients display a constitutive presence in the circulation. To understand the molecular basis for this, we have used microarray technology to analyze the transcriptional differences between dividing and quiescent, normal, and CML-derived CD34+ cells. Our data show a remarkable transcriptional similarity between normal and CML dividing cells, suggesting that the effects of BCR-ABL on the CD34+ cell transcriptome are more limited than previously thought. In addition, we show that quiescent CML cells are more similar to their dividing counterparts than quiescent normal cells are to theirs. We also show these transcriptional differences to be reflected in the altered proliferative activity of normal and CML CD34+ cells. Of the most interest is that the major class of genes that is more abundant in the quiescent cells compared with the dividing cells encodes members of the chemokine family. We propose a role for chemokines expressed by quiescent HSC in the orchestration of CD34+ cell mobilization. Disclosure of potential conflicts of interest is found at the end of this article.


systematic_name: M13254
exact_source: Table 4S: Ratio NDvCG > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in quescent CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloblastic leukemia) patients compared to the dividing cells from normal donors.

description_full:
  Quiescent and dividing hemopoietic stem cells (HSC) display marked differences in their ability to move between the peripheral circulation and the bone marrow. Specifically, long-term engraftment potential predominantly resides in the quiescent HSC subfraction, and G-CSF mobilization results in the preferential accumulation of quiescent HSC in the periphery. In contrast, stem cells from chronic myeloid leukemia (CML) patients display a constitutive presence in the circulation. To understand the molecular basis for this, we have used microarray technology to analyze the transcriptional differences between dividing and quiescent, normal, and CML-derived CD34+ cells. Our data show a remarkable transcriptional similarity between normal and CML dividing cells, suggesting that the effects of BCR-ABL on the CD34+ cell transcriptome are more limited than previously thought. In addition, we show that quiescent CML cells are more similar to their dividing counterparts than quiescent normal cells are to theirs. We also show these transcriptional differences to be reflected in the altered proliferative activity of normal and CML CD34+ cells. Of the most interest is that the major class of genes that is more abundant in the quiescent cells compared with the dividing cells encodes members of the chemokine family. We propose a role for chemokines expressed by quiescent HSC in the orchestration of CD34+ cell mobilization. Disclosure of potential conflicts of interest is found at the end of this article.


systematic_name: M19476
exact_source: Table 5S: Ratio CDvND > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in dividing CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloid leukemia) patients compared to the dividing cells from normal donors.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M19367
exact_source: Table 5S: Ratio NDvCD > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in dividing CD34+ [GeneID=8842] cells isolated from peripheral blood of CML (chronic myeloid leukemia) patients compared to the dividing cells from normal donors.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M4235
exact_source: Table 6S: Ratio NGvCD > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in quiescent CD34+ [GeneID=8842] cells isolated from peripheral blood of normal donors compared to the dividing cells from CML (chronic myeloid leukemia) patients.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M4406
exact_source: Table 7S: Ratio NG/ND > 3
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in quiescent vs dividing CD34+ [GeneID=8842] cells isolated from peripheral blood of normal donors.

description_full:
[cell repeats an earlier one in this file: 1512 characters]


systematic_name: M8818
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in endometroid endometrial tumors from patients with lymph node metastases compared to those without the metastases.

description_full:
  PURPOSE: To characterize the gene expression profiles of endometrioid endometrial cancers associated with lymph node metastasis in an effort to identify genes associated with metastatic spread. EXPERIMENTAL DESIGN: Tumors from 41 patients with endometrioid endometrial cancer grossly confined to the uterine cavity were evaluated. Positive lymph nodes were noted in 12 of 41 patients. RNA was analyzed for gene expression using the Affymetrix HG133A and HG133B GeneChip set, representing 45,000 array features covering >28,000 UniGene clusters. Data analysis was done using multidimensional scaling, binary comparison, and hierarchical clustering. Gene expression for several differentially expressed genes was examined using quantitative PCR. RESULTS: Gene expression data was obtained from 30,964 genes that were detected in at least 5% of the cases. Supervised analysis of node-positive versus node-negative cases indicated that 450 genes were significantly differentially expressed between the two classes at P < 0.005, 81 of which were differentially expressed by at least 2-fold at P < 0.005. Overexpressed genes included two cell cycle checkpoint genes, CDC2 and MAD2L1, which have previously been described in association with lymph node metastasis in other cancer types. The ZIC2 zinc finger gene was overexpressed in endometrial cancers with positive nodes versus those with negative nodes. CONCLUSION: Gene expression profiling of the primary tumors in patients with endometrioid endometrial cancers seems promising for identifying genes associated with lymph node metastasis. Future studies should address whether the status of nodal metastasis can be determined from the expression profiles of preoperative tissue specimens.


systematic_name: M10091
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mucinous ovarian carcinoma tumors of low malignant potential (LMP) compared to normal ovarian surface epithelium tissue.

description_full:
  PURPOSE: To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. EXPERIMENTAL DESIGN: Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. RESULTS: Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. CONCLUSIONS: These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.


systematic_name: M707
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in mucinous ovarian carcinoma tumors of grades 1 and 2 compared to the normal ovarian survace epithelium tissue.

description_full:
  PURPOSE: To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. EXPERIMENTAL DESIGN: Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. RESULTS: Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. CONCLUSIONS: These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.


systematic_name: M12002
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE3202
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in H720 cells (lung cancer) after treatment with L663536 (MK886) [PubChem=105049], an inhibitor of leukotriene biosynthesis.

description_full:
  The small molecular inhibitor MK886 is known to block 5-lipoxygenase-activating protein ALOX5AP and shows antitumor activity in multiple human cell lines. The broad antitumor therapeutic window reported in vivo for MK886 in rodents supports further consideration of this structural class. Better understanding of the mode of action of the drug is important for application in humans to take place. Affymetrix microarray study was conducted to explore MK886 pharmacologic mechanism. Ingenuity Pathway Analysis software was applied to validate the results at the transcriptional level by putting them in the context of an experimental proteomic network. Genes most affected by MK886 included actin B and focal adhesion components. A subsequent National Cancer Institute-60 panel study, RT-PCR validation followed by confocal microscopy, and Western blotting also pointed to actin B down-regulation, filamentous actin loss, and disorganization of the transcription machinery. In agreement with these observations, MK886 was found to enhance the effect of UV radiation in H720 lung cancer cell line. In light of the modification of cytoskeleton and cell motility by lipid phosphoinositide 3-kinase products, MK886 interaction with actin B might be biologically important. The low toxicity of MK886 in vivo was modeled and explained by binding and transport by dietary lipids. The rate of lipid absorbance is generally higher for tumors, suggesting a promise of a targeted liposome-based delivery system for this drug. These results suggest a novel antitumor pharmacologic mechanism.


systematic_name: M14796
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE3202
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in H720 cells (lung cancer) after treatment with L663536 (MK886) [PubChem=105049], an inhibitor of leukotriene biosynthesis.

description_full:
  The small molecular inhibitor MK886 is known to block 5-lipoxygenase-activating protein ALOX5AP and shows antitumor activity in multiple human cell lines. The broad antitumor therapeutic window reported in vivo for MK886 in rodents supports further consideration of this structural class. Better understanding of the mode of action of the drug is important for application in humans to take place. Affymetrix microarray study was conducted to explore MK886 pharmacologic mechanism. Ingenuity Pathway Analysis software was applied to validate the results at the transcriptional level by putting them in the context of an experimental proteomic network. Genes most affected by MK886 included actin B and focal adhesion components. A subsequent National Cancer Institute-60 panel study, RT-PCR validation followed by confocal microscopy, and Western blotting also pointed to actin B down-regulation, filamentous actin loss, and disorganization of the transcription machinery. In agreement with these observations, MK886 was found to enhance the effect of UV radiation in H720 lung cancer cell line. In light of the modification of cytoskeleton and cell motility by lipid phosphoinositide 3-kinase products, MK886 interaction with actin B might be biologically important. The low toxicity of MK886 in vivo was modeled and explained by binding and transport by dietary lipids. The rate of lipid absorbance is generally higher for tumors, suggesting a promise of a targeted liposome-based delivery system for this drug. These results suggest a novel antitumor pharmacologic mechanism.


systematic_name: M12084
exact_source: Table 1
source_species_code: HS
GEO_id: GSE3629
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in non-neoplastic rectal mucosa samples from patients having cancer associated with ulcerative collitis, compared to those who did not have the cancer.

description_full:
  PURPOSE: Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients. EXPERIMENTAL DESIGN: Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group). RESULTS: By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor-related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively. CONCLUSIONS: These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.


systematic_name: M15662
exact_source: Table 1
source_species_code: HS
GEO_id: GSE3629
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in non-neoplastic rectal mucosa samples from patients having cancer associated with ulcerative collitis, compared to those who did not have the cancer.

description_full:
  PURPOSE: Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients. EXPERIMENTAL DESIGN: Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group). RESULTS: By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor-related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively. CONCLUSIONS: These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.


systematic_name: M3910
exact_source: Table 5S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in poorly differentiated thyroid carcinoma (PDTC) compared to anaplastic thyroid carcinoma (ATC).

description_full:
  Information on gene alterations associated to poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) is scarce. Using human cancer cell lines as a tool for gene discovery, we performed a cytogenetic and oligo-array analysis in five new cell lines derived from two PDTC and three ATC. In PDTC we evidenced, as important, the involvement of the MAPK/ERK kinase pathway, and downregulation of a group of suppressor genes that include E-cadherin. In ATC, downregulation of a specific group of oncosuppressor genes was also observed. Our ATC cell lines presented chromosomal markers of gene amplification, and we were able to identify for the first time the nature of the involved amplicon target genes. We found that the main molecular differences between the two cell line types were related to signal transduction pathways, cell adhesion and motility process. TaqMan experiments performed for five amplicon target genes and for two genes, which allowed a clear distinction between ATC and PDTC: CDH13 and PLAU corroborated array results, not only in the cell lines, but also in an additional set of primary 14 PDTC and three ATC. We suggest that our findings may represent new tools for the development of more effective therapies to the hitherto untreatable ATC.


systematic_name: M9814
exact_source: Table 5S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in poorly differentiated thyroid carcinoma (PDTC) compared to anaplastic thyroid carcinoma (ATC).

description_full:
  Information on gene alterations associated to poorly differentiated (PDTC) and anaplastic thyroid carcinomas (ATC) is scarce. Using human cancer cell lines as a tool for gene discovery, we performed a cytogenetic and oligo-array analysis in five new cell lines derived from two PDTC and three ATC. In PDTC we evidenced, as important, the involvement of the MAPK/ERK kinase pathway, and downregulation of a group of suppressor genes that include E-cadherin. In ATC, downregulation of a specific group of oncosuppressor genes was also observed. Our ATC cell lines presented chromosomal markers of gene amplification, and we were able to identify for the first time the nature of the involved amplicon target genes. We found that the main molecular differences between the two cell line types were related to signal transduction pathways, cell adhesion and motility process. TaqMan experiments performed for five amplicon target genes and for two genes, which allowed a clear distinction between ATC and PDTC: CDH13 and PLAU corroborated array results, not only in the cell lines, but also in an additional set of primary 14 PDTC and three ATC. We suggest that our findings may represent new tools for the development of more effective therapies to the hitherto untreatable ATC.


systematic_name: M13944
exact_source: Table 1S
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in TMX2-28 cells (breast cancer) which do not express ESR1 [GeneID=2099]) compared to the parental MCF7 cells which do.

description_full:
  We have used a novel variant of the human oestrogen receptor (ER)-positive MCF-7 cell line, TMX2-28, as a model to study breast cancer. TMX2-28 cells show no detectable levels of mRNA or protein expression for the ER and express basal cytokeratins (CKs) 5, 14, and 17. cDNA microarray comparison between TMX2-28 and its parent cell line, MCF-7, identified 1402 differentially expressed transcripts, one of which was, phospholipase D1 (PLD1). Using real-time RT-PCR, we confirmed that PLD1 mRNA levels are 10-fold higher in TMX2-28 cells than in MCF-7 cells. We next examined PLD1 expression in human breast carcinomas. Phospholipase D1 mRNA levels were higher in breast tumours that expressed high-mRNA levels of basal CKs 5 and/or 17, but PLD1 mRNA levels were not significantly higher in ER-negative tumours. Phospholipase D1 protein was overexpressed in 10 of 42 (24%) breast tumours examined by IHC. Phospholipase D1 was overexpressed in 6 of 31 ER-positive tumours and 4 of 11 ER-negative tumours. Phospholipase D1 was overexpressed in three of the four tumours that showed high CK5/17 expression. Five PLD1-positive tumours were negative for phospho-Akt expression, but positive for phospho-mammalian target of rapamycin (mTOR) expression. The other five PLD1-positive breast tumours showed positive expression for phospho-Akt; however, only two of these cases were positive for phospho-mTOR. In this study, we report that PLD1 and phospho-mTOR are coexpressed in a subset of phospho-Akt-negative breast carcinomas.


systematic_name: M14577
exact_source: Table 3S: M >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in monocytes isolated from peripheral blood samples of Sezary syndrom patients compared to those from healthy normal donors.

description_full:
  PURPOSE: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes. EXPERIMENTAL DESIGN: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4(+) cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression. RESULTS: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations. CONCLUSIONS: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.


systematic_name: M18968
exact_source: Table 3S: M =< -1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in monocytes isolated from peripheral blood samples of Sezary syndrom patients compared to those from healthy normal donors.

description_full:
  PURPOSE: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes. EXPERIMENTAL DESIGN: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4(+) cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression. RESULTS: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations. CONCLUSIONS: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.


systematic_name: M5570
exact_source: Table 4S: M =< -1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in lesional skin biopsies from mycosis fundoides patients compared to the normal skin samples.

description_full:
  PURPOSE: Increased production of Th2 cytokines characterizes Sezary syndrome, the leukemic form of cutaneous T-cell lymphomas (CTCL). To identify the molecular background and to study whether shared by the most common CTCL subtype, mycosis fungoides, we analyzed the gene expression profiles in both subtypes. EXPERIMENTAL DESIGN: Freshly isolated cells from 30 samples, representing skin, blood, and enriched CD4(+) cell populations of mycosis fungoides and Sezary syndrome, were analyzed with Affymetrix (Santa Clara, CA) oligonucleotide microarrays, quantitative PCR, or immunohistochemistry. The gene expression profiles were combined with findings of comparative genomic hybridization of the same samples to identify chromosomal changes affecting the aberrant gene expression. RESULTS: We identified a set of Th1-specific genes [e.g., TBX21 (T-bet), NKG7, and SCYA5 (RANTES)] to be down-regulated in Sezary syndrome as well as in a proportion of mycosis fungoides samples. In both Sezary syndrome and mycosis fungoides blood samples, the S100P and LIR9 gene expression was up-regulated. In lesional skin, IL7R and CD52 were up-regulated. Integration of comparative genomic hybridization and transcriptomic data identified chromosome arms 1q, 3p, 3q, 4q, 12q, 16p, and 16q as likely targets for new CTCL-associated gene aberrations. CONCLUSIONS: Our findings revealed several new genes involved in CTCL pathogenesis and potential therapeutic targets. Down-regulation of a set of genes involved in Th1 polarization, including the major Th1-polarizing factor, TBX21, was for the first time associated with CTCL. In addition, a plausible explanation for the proliferative response of CTCL cells to locally produced interleukin-7 was revealed.


systematic_name: M19849
exact_source: Table 5S: M=< -1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in T helper cells (defines as CD4+) isolated from patients with mucosis fungoides compared to those from normal control donors.

description_full:
[cell repeats an earlier one in this file: 1743 characters]


systematic_name: M6714
exact_source: Table 6S: M >= 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in monocytes isolated from peripheral blood samples of patients with mucosis fungoides compared to those from normal healthy donors.

description_full:
[cell repeats an earlier one in this file: 1743 characters]


systematic_name: M12073
exact_source: Table 6S: M =< -1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in monocytes isolated from peripheral blood samples of patients with mucosis fungoides compared to those from normal healthy donors.

description_full:
[cell repeats an earlier one in this file: 1743 characters]


systematic_name: M4100
exact_source: Table 3S: FC > 1
source_species_code: HS
GEO_id: GSE2509,GSE1323
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in polysomal and total RNA samples from SW480 cells (primary colorectal carcinoma, CRC) compared to the SW620 cells (lymph node metastasis from the same individual).

description_full:
  Tumour onset and progression are due to the accumulation of genomic lesions, which alter gene expression and ultimately proteome activities. These lesions are thought to affect primarily the transcriptional control of gene expression. In the present study, we aimed at evaluating the genome-wide occurrence of alterations in the translational control exploiting an isogenic, phenotypically validated cellular model of colorectal cancer (CRC) transition from invasive carcinoma to metastasis. In this model, microarray profiling shows that changes in the level of messenger ribonucleic acid (mRNA) association with polysomes occur more than 2-fold than changes in the level of total cellular mRNA. When common to both the total and polysomal compartments, these changes are also homodirectional, being amplified in magnitude at the polysomal level. Comparison between the transcriptional and the translational fluctuations revealed distinct signatures of statistically over-represented gene functions, involving the program of cell proliferation for both levels of analysis, while the apoptosis and the translation programs were affected mainly at translation. Looking for an upstream determinant of translational deregulation, we found an increase in the hyperphosphorylated form of the 4E-BP1 protein in the metastatic cell line, possibly resulting in an increased activation of cap-dependent translation due to increased activity of the eIF4E protein. Analysis of the distribution profiles for the 5' untranslated region (5'-UTR) length of the changed genes showed an association between longer 5'-UTRs and the probability for the relevant gene to be altered translationally, consistent with enhanced eIF4E function. This genome-wide analysis is in favour of a model of profound alteration of translational control in late CRC progression. It also suggests polysomal mRNA profiles as a new, informative dimension for the study of transcriptome imbalance in cancer.


description_brief: Genes up-regulated in MCF7 cells (breast cancer) by IGF1 and IGF2 [GeneID=3479;3481].
systematic_name: M16574
exact_source: Tables 2-5: IGF1 fold regulation > 0
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Insulin-like growth factor (IGF) signaling is a key regulator of breast development and breast cancer. We have analyzed the expression of the IGF signaling cascade in 17 human breast cancer and 4 mammary epithelial cell lines. Five cell lines expressed high levels of IGF1 receptor, insulin (INS)/IGF receptor substrate 1, IGF-binding proteins 2 and 4, as well as the estrogen receptor (ESR), indicating a co-activation of IGF and ESR signaling. Next, we stably overexpressed IGF1 and IGF2 in MCF7 breast cancer cells, which did not affect their epithelial characteristics and the expression and localization of the epithelial marker genes E-cadherin and beta-catenin. Conversely, IGF1 and IGF2 overexpression potently increased cellular proliferation rates and the efficiency of tumor formation in mouse xenograft experiments, whereas the resistance to chemotherapeutic drugs such as taxol was unaltered. Expression profiling of overexpressing cells with whole-genome oligonucleotide microarrays revealed that 21 genes were upregulated >2-fold by both IGF1 and IGF2, 9 by IGF1, and 9 by IGF2. Half of the genes found to be upregulated are involved in transport and biosynthesis of amino acids, including several amino acid transport proteins, argininosuccinate and asparagine synthetases, and methionyl-tRNA synthetase. Upregulation of these genes constitutes a novel mechanism apparently contributing to the stimulatory effects of IGF signaling on the global protein synthesis rate. We conclude that the induction of cell proliferation and tumor formation by long-term IGF stimulation may primarily be due to anabolic effects, in particular increased amino acid production and uptake.


systematic_name: M19218
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in HET1A cells (esophagus epithelium) engineered to stably express CDX2 [GeneID=1045].

description_full:
  Caudal-related homeobox 2 (Cdx2) has been suggested as an early marker of Barrett's esophagus (BE), which is the premalignant lesion of esophageal adenocarcinoma (EAC). However, the mechanism of ectopic Cdx2 expression in the esophageal epithelial cells and its role in the development of BE remained unclear. RT-PCR, pyrosequencing and methylation-specific PCR were used to determine expression and promoter methylation of Cdx2 in human esophageal epithelial cells (HET1A and SEG1) after treatment with 5-aza-2'-deoxycytidine (DAC), acid, bile acids and their combination. HET1A cells with stable transfection of Cdx2 were characterized for morphology and gene expression profiles with Affymetrix array. We found Cdx2 was expressed in most human EAC cell lines, but not in squamous epithelial cell lines. DAC-induced demethylation and expression of Cdx2 in HET1A and SEG1 cells, and treatment with a DNA methylating agent counteracted the effect of DAC. Treatment of HET1A and SEG1 cells with acid, bile acids or both also resulted in promoter demethylation and expression of Cdx2. HET1A cells with stable transfection of human Cdx2 formed crypt-like structures in vitro. Microarray analysis and quantitative real-time PCR showed that stable transfection of Cdx2 up-regulated differentiation markers of intestinal columnar epithelial cells and goblet cells in HET1A cells. This may be partially due to modulation of Notch signaling pathway, as western blotting confirmed down-regulation of Hes1 and up-regulation of Atoh1 and Muc2. Our data suggest that exposure to acid and/or bile acids may activate Cdx2 expression in human esophageal epithelial cells through promoter demethylation, and ectopic Cdx2 expression in esophageal squamous epithelial cells may contribute to intestinal metaplasia of the esophagus.


systematic_name: M18134
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE4342
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in NSCLC (non-small cell lung carcinoma) cell lines resistant to gefitinib [PubChem=123631] compared to the sensitive ones.

description_full:
  Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) produce objective responses in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), and about half of all treated patients progress within 6 weeks of instituting therapy. Because the target of these agents is known, it should be possible to develop biological predictors of response, but EGFR protein levels have not been proven useful as a predictor of TKI response in patients and the mechanism of primary resistance is unclear. We used microarray gene expression profiling to uncover a pattern of gene expression associated with sensitivity to EGFR-TKIs by comparing NSCLC cell lines that were either highly sensitive or highly resistant to gefitinib. This sensitivity-associated expression profile was used to predict gefitinib sensitivity in a panel of NSCLC cell lines with known gene expression profiles but unknown gefitinib sensitivity. Gefitinib sensitivity was then determined for members of this test panel, and the microarray-based sensitivity prediction was correct in eight of nine NSCLC cell lines. Gene and protein expression differences were confirmed with a combination of quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry. This gene expression pattern related to gefitinib sensitivity was independent from sensitivity associated with EGFR mutations. Several genes associated with sensitivity encode proteins involved in HER pathway signaling or pathways that interrelate to the HER signaling pathway. Some of these genes could be targets of pharmacologic interventions to overcome primary resistance.


systematic_name: M19828
exact_source: Table 1: Upregulated
source_species_code: HS
GEO_id: GSE2243
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in K562 (chronic myelogenous leukemia, CML) cells engineered to stably express RIZ1 [GeneID=7799].

description_full:
  RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.


systematic_name: M4364
exact_source: Table 1: Downregulated
source_species_code: HS
GEO_id: GSE2243
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in K562 (chronic myelogenous leukemia, CML) cells engineered to stably express RIZ1 [GeneID=7799].

description_full:
  RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.


systematic_name: M2626
exact_source: Table 1: Mean fold change > 0
source_species_code: HS
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in C666-1 cells (nasopharyngeal carcinoma) by stable expression of RASSF1 [GeneID=11186].

description_full:
  RASSF1A is a tumor suppressor gene on 3p21.3 frequently inactivated by promoter hypermethylation in nasopharyngeal carcinoma (NPC). To identify RASSF1A target genes in NPC, we have investigated the expression profile of the stable RASSF1A transfectants and controls by high-density oligonucleotide array. A total of 57 genes showed differential expression in the RASSF1A-expressing cells. These RASSF1A target genes were involved in multiple cellular regulatory processes such as transcription, signal transduction, cell adhesion and RNA processing. The RASSF1A-modulated expression of eight selected genes with the highest fold changes (ATF5, TCRB, RGS1, activin betaE, HNRPH1, HNRPD, Id2 and CKS2) by RASSF1A was confirmed in both stable and transient transfectants. Compared with the RASSF1A transfectants, an inverse expression pattern of activin betaE, Id2 and ATF5 was shown in the immortalized nasopharyngeal epithelial cells treated with siRNA against RASSF1A. The findings imply that the expression of activin betaE, Id2 and ATF5 was tightly regulated by RASSF1A and may associate with its tumor suppressor function. Strikingly, overexpression of Id2 is common in NPC and RASSF1A-induced repression of Id2 was mediated by the overexpression of activin betaE. The results suggest a novel RASSF1A pathway in which both activin betaE and Id2 are involved.


systematic_name: M905
exact_source: Table 1: Mean fold change < 0
source_species_code: HS
contributor: Lauren Kazmierski
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in C666-1 cells (nasopharyngeal carcinoma) by stable expression of RASSF1 [GeneID=11186].

description_full:
  RASSF1A is a tumor suppressor gene on 3p21.3 frequently inactivated by promoter hypermethylation in nasopharyngeal carcinoma (NPC). To identify RASSF1A target genes in NPC, we have investigated the expression profile of the stable RASSF1A transfectants and controls by high-density oligonucleotide array. A total of 57 genes showed differential expression in the RASSF1A-expressing cells. These RASSF1A target genes were involved in multiple cellular regulatory processes such as transcription, signal transduction, cell adhesion and RNA processing. The RASSF1A-modulated expression of eight selected genes with the highest fold changes (ATF5, TCRB, RGS1, activin betaE, HNRPH1, HNRPD, Id2 and CKS2) by RASSF1A was confirmed in both stable and transient transfectants. Compared with the RASSF1A transfectants, an inverse expression pattern of activin betaE, Id2 and ATF5 was shown in the immortalized nasopharyngeal epithelial cells treated with siRNA against RASSF1A. The findings imply that the expression of activin betaE, Id2 and ATF5 was tightly regulated by RASSF1A and may associate with its tumor suppressor function. Strikingly, overexpression of Id2 is common in NPC and RASSF1A-induced repression of Id2 was mediated by the overexpression of activin betaE. The results suggest a novel RASSF1A pathway in which both activin betaE and Id2 are involved.


systematic_name: M17211
exact_source: Figure 6A: Down-Regulated TF
source_species_code: HS
contributor: Aravind Subramanian
contrib_organization: MSigDB Team
description_brief:
  Transcription factors down-regulated in LNCaP cells (prostate cancer) by expression of GR [GeneID=2908] off a lentiviral vector.

description_full:
  Glucocorticoids are extensively used in combination chemotherapy of advanced prostate cancer (PC). Little is known, however, about the status of the glucocorticoid receptor (GR) in PC. We evaluated over 200 prostate samples and determined that GR expression was strongly decreased or absent in 70-85% of PC. Similar to PC tumors, some PC cell lines, including LNCaP, also lack GR. To understand the role of GR, we reconstituted its expression in LNCaP cells using lentiviral approach. Treatment of LNCaP-GR cells with the glucocorticoids strongly inhibited proliferation in the monolayer cultures and blocked anchorage-independent growth. This was accompanied by upregulation of p21 and p27, down-regulation of cyclin D1 expression and c-Myc phosphorylation. Importantly, the activation of GR resulted in normalized expression of PC markers hepsin, AMACR, and maspin. On the signaling level, GR decreased expression and inhibited activity of the MAP-kinases (MAPKs) including p38, JNK/SAPK, Mek1/2 and Erk1/2. We also found that activation of GR inhibited activity of numerous transcription factors (TF) including AP-1, SRF, NF-kappaB, p53, ATF-2, CEBPalpha, Ets-1, Elk-1, STAT1 and others, many of which are regulated via MAPK cascade. The structural analysis of hepsin and AMACR promoters provided the mechanistic rationale for PC marker downregulation by glucocorticoids via inhibition of specific TFs. Our data suggest that GR functions as a tumor suppressor in prostate, and inhibits multiple signaling pathways and transcriptional factors involved in proliferation and transformation.


systematic_name: M19275
exact_source: Table 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated by UV-irradiation in cervical cancer cells after knockdown of CDKN2A [GeneID=1029].

description_full:
  p16(INK4A) (p16) has been suggested to be an early biomarker for the detection of cervical cancer. However, its functional role in cervical cancer is not well characterized. In this study, we reported the consistent and significant upregulation of p16 in cervical cancer tissues when compared to both matched non-tumourous tissues of the same patient and normal cervical tissues from non-cancer patients. We have employed p16 small interfering RNA (siRNA) to dissect the role of p16 in cervical carcinogenesis. Although the silencing of p16 was accompanied by the upregulation of p53, p21 and RB in the p16 siRNA-transfected cells, no significant effect on cell cycle progression was observed. When the p16 siRNA-silenced cells were subjected to DNA damage stress including ultraviolet-irradiation and cisplatin treatments, a significantly higher percentage of apoptotic cells could be observed in the p16-siRNA silenced cells compared to control siRNA-treated cells. Moreover, induction of apoptosis was associated with the activation of p53 through phosphorylation, and this process, when studied by gene profiling experiments, involved both the intrinsic and extrinsic apoptotic pathways. The observation that silencing of p16 expression augments DNA damage-induced apoptosis in cervical cancer cells offers alternative strategies for anti-cancer therapies for human cervical cancer.


systematic_name: M2250
exact_source: Table 2AS
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes whose expression profile is specific to Custer I of urothelial cell carcinoma (UCC) tumors.

description_full:
  We used gene expression profiling, mutation analyses of FGFR3 and TP53, and LOH analyses of chromosome 9 and the TP53 region on chromosome arm 17p, to molecularly characterize 75 Ta and T1 bladder carcinomas. We identified four major cellular processes related to cell cycle, protein synthesis, immune response, and extra cellular components that contribute to the expressional heterogeneity of early-stage urothelial cell carcinoma (UCC). Activating FGFR3 mutations were found at the highest frequency in G1 tumors (80%), and showed a strong correlation with FGFR3 expression. In contrast, G3 tumors displayed mutations in less than 10% of the cases and a low level of FGFR3 expression. Even though LOH on chromosome 9 was not associated with any specific expression pattern, our data indicate that loss of chromosome 9 is associated with tumor development rather than initiation. The combined analyses suggest the existence of two types of UCC tumors, one which is characterized by FGFR3 mutation or expression, high expression of protein synthesis genes, and low expression of cell cycle genes. Furthermore, the presented data underscore FGFR3 receptor involvement in urothelial cell transformation as the presence of FGFR3 mutations has a major impact on the global gene expression profile of bladder carcinomas.


systematic_name: M12889
exact_source: Table 2CS
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression profile is specific to Cluster IIa of urothelial cell carcinoma (UCC) tumors.

description_full:
  We used gene expression profiling, mutation analyses of FGFR3 and TP53, and LOH analyses of chromosome 9 and the TP53 region on chromosome arm 17p, to molecularly characterize 75 Ta and T1 bladder carcinomas. We identified four major cellular processes related to cell cycle, protein synthesis, immune response, and extra cellular components that contribute to the expressional heterogeneity of early-stage urothelial cell carcinoma (UCC). Activating FGFR3 mutations were found at the highest frequency in G1 tumors (80%), and showed a strong correlation with FGFR3 expression. In contrast, G3 tumors displayed mutations in less than 10% of the cases and a low level of FGFR3 expression. Even though LOH on chromosome 9 was not associated with any specific expression pattern, our data indicate that loss of chromosome 9 is associated with tumor development rather than initiation. The combined analyses suggest the existence of two types of UCC tumors, one which is characterized by FGFR3 mutation or expression, high expression of protein synthesis genes, and low expression of cell cycle genes. Furthermore, the presented data underscore FGFR3 receptor involvement in urothelial cell transformation as the presence of FGFR3 mutations has a major impact on the global gene expression profile of bladder carcinomas.


systematic_name: M11238
exact_source: Table 2GS
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes whose expression profile is specific to Cluster III of urothelial cell carcinoma (UCC) tumors.

description_full:
[cell repeats an earlier one in this file: 1316 characters]


systematic_name: M1177
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE2138
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in colorectal carcinoma samples positive for MSI (microsatellite instability) compared to the MSI negative ones.

description_full:
  Mutation or epigenetic silencing of mismatch repair genes, such as MLH1 and MSH2, results in microsatellite instability (MSI) in the genome of a subset of colorectal carcinomas (CRCs). However, little is yet known of genes that directly contribute to tumor formation in such cancers. To characterize MSI-dependent changes in gene expression, we have now compared transcriptomes between fresh CRC specimens positive or negative for MSI (n=10 for each) with the use of high-density oligonucleotide microarrays harboring >44,000 probe sets. Correspondence analysis of the expression patterns of isolated MSI-associated genes revealed that the transcriptome of MSI+ CRCs is clearly distinct from that of MSI- CRCs. Such MSI-associated genes included that for AXIN2, an important component of the WNT signaling pathway. AXIN2 was silenced, apparently as a result of extensive methylation of its promoter region, specifically in MSI+ CRC specimens. Forced expression of AXIN2, either by treatment with 5'-azacytidine or by transfection with AXIN2 cDNA, resulted in rapid cell death in an MSI+ CRC cell line. These data indicate that epigenetic silencing of AXIN2 is specifically associated with carcinogenesis in MSI+ CRCs.


systematic_name: M16515
exact_source: Table 1: RAD001-insensitive
source_species_code: HS
GEO_id: GSE1379
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes in the AKT1 [GeneID=207] pathway which are independent of MTOR [GeneID=2475], insensitive to RAD001 (everolimus) [PubChem=6442177].

description_full:
  The Akt pathway is commonly deregulated in many cancers. Clinical trials are currently underway to test the effectiveness of breast cancer treatment by inhibition of various Akt pathway intermediates. A set of genes induced by Akt in a transgenic mouse model, a subset of which were sensitive to mammalian target of rapamycin (mTOR) inhibitor RAD001, was examined in five public gene expression profile data sets of clinical breast tumor specimens (representing >1000 different samples in all). In each of the clinical data sets, the Akt mouse model genes as a group were significantly overexpressed in human tumors having high levels of AKT1 mRNA. The subset of genes both upregulated by Akt and dependent on mTOR activity were associated with estrogen receptor-negative status, higher grade, increasing tumor size and poor prognosis in multiple patient cohorts; these associations were either not present or not as strong for the Akt-induced, mTOR-independent genes or for AKT1 expression alone. The genes shown here to be relevant to Akt-mTOR both experimentally and pathologically have the potential for use in a molecular diagnostic to determine which patients should receive mTOR antagonist treatment.


systematic_name: M8629
exact_source: Table 1
source_species_code: HS
GEO_id: E-UCON-1
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the breast cancer prognostic signature of 70 genes that significantly correlated with survival.

description_full:
  Prognostic signatures in breast cancer derived from microarray expression profiling have been reported by two independent groups. These signatures, however, have not been validated in external studies, making clinical application problematic. We performed microarray expression profiling of 135 early-stage tumors, from a cohort representative of the demographics of breast cancer. Using a recently proposed semisupervised method, we identified a prognostic signature of 70 genes that significantly correlated with survival (hazard ratio (HR): 5.97, 95% confidence interval: 3.0-11.9, P = 2.7e-07). In multivariate analysis, the signature performed independently of other standard prognostic classifiers such as the Nottingham Prognostic Index and the 'Adjuvant!' software. Using two different prognostic classification schemes and measures, nearest centroid (HR) and risk ordering (D-index), the 70-gene classifier was also found to be prognostic in two independent external data sets. Overall, the 70-gene set was prognostic in our study and the two external studies which collectively include 715 patients. In contrast, we found that the two previously described prognostic gene sets performed less optimally in external validation. Finally, a common prognostic module of 29 genes that associated with survival in both our cohort and the two external data sets was identified. In spite of these results, further studies that profile larger cohorts using a single microarray platform, will be needed before prospective clinical use of molecular classifiers can be contemplated.


description_brief: Genes from common regions of gains observed in more than 15% of 148 primary breast cancer tumors.
systematic_name: M672
exact_source: Fig 2b: gains
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  We analysed 148 primary breast cancers using BAC-arrays containing 287 clones representing cancer-related gene/loci to obtain genomic molecular portraits. Gains were detected in 136 tumors (91.9%) and losses in 123 tumors (83.1%). Eight tumors (5.4%) did not have any genomic aberrations in the 281 clones analysed. Common (more than 15% of the samples) gains were observed at 8q11-qtel, 1q21-qtel, 17q11-q12 and 11q13, whereas common losses were observed at 16q12-qtel, 11ptel-p15.5, 1p36-ptel, 17p11.2-p12 and 8ptel-p22. Patients with tumors registering either less than 5% (median value) or less than 11% (third quartile) total copy number changes had a better overall survival (log-rank test: P=0.0417 and P=0.0375, respectively). Unsupervised hierarchical clustering based on copy number changes identified four clusters. Women with tumors from the cluster with amplification of three regions containing known breast oncogenes (11q13, 17q12 and 20q13) had a worse prognosis. The good prognosis group (Nottingham Prognostic Index (NPI) <or=3.4) tumors had frequent loss of 16q24-qtel. Genes significantly associated with estrogen receptor (ER), Grade and NPI were used to build k-nearest neighbor (KNN) classifiers that predicted ER, Grade and NPI status in the test set with an average misclassification rate of 24.7, 25.7 and 35.7%, respectively. These data raise the prospect of generating a molecular taxonomy of breast cancer based on copy number profiling using tumor DNA, which may be more generally applicable than expression microarray analysis.


description_brief: Genes down-regulated in uterine fibroids vs normal myometrium samples.
systematic_name: M13879
exact_source: Table 3
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Uterine fibroids are some of the most common tumours of females, but relatively little is known about their molecular basis. Several studies have suggested that deletions on chromosome 7q could have a role in fibroid formation. We analysed 165 sporadic uterine fibroids to define a small 3.2 megabase (Mb) commonly deleted region on 7q22.3-q31.1, flanked by clones AC005070 and AC007567. We also used oligonucleotide microarrays to compare the expression profiles of 10 samples of normal myometrium and 15 fibroids, nine of which displayed 7q-deletions. Activating transcription factor 3, patched homolog (Drosophila), homeo box A5, death-associated protein kinase 1, and retinoic acid receptor responder 3 were downregulated, and excision repair crosscomplementing 3, transcription factor AP-2 gamma and protein kinase C beta 1 were upregulated in fibroids. New pathways were discovered related to fibroid formation. The presence or absence of 7q-deletions did not dramatically affect the global expression pattern of the tumours; changes, however, were observed in genes related to vesicular transport and nucleic acid binding.


systematic_name: M1752
exact_source: Table 2S: fold change > 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in uterine fibroids with deletions in the 7q region vs those without the deletion.

description_full:
  Uterine fibroids are some of the most common tumours of females, but relatively little is known about their molecular basis. Several studies have suggested that deletions on chromosome 7q could have a role in fibroid formation. We analysed 165 sporadic uterine fibroids to define a small 3.2 megabase (Mb) commonly deleted region on 7q22.3-q31.1, flanked by clones AC005070 and AC007567. We also used oligonucleotide microarrays to compare the expression profiles of 10 samples of normal myometrium and 15 fibroids, nine of which displayed 7q-deletions. Activating transcription factor 3, patched homolog (Drosophila), homeo box A5, death-associated protein kinase 1, and retinoic acid receptor responder 3 were downregulated, and excision repair crosscomplementing 3, transcription factor AP-2 gamma and protein kinase C beta 1 were upregulated in fibroids. New pathways were discovered related to fibroid formation. The presence or absence of 7q-deletions did not dramatically affect the global expression pattern of the tumours; changes, however, were observed in genes related to vesicular transport and nucleic acid binding.


systematic_name: M13327
exact_source: Table 2S: fold change < 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in uterine fibroids with deletions in the 7q region vs those without the deletion.

description_full:
  Uterine fibroids are some of the most common tumours of females, but relatively little is known about their molecular basis. Several studies have suggested that deletions on chromosome 7q could have a role in fibroid formation. We analysed 165 sporadic uterine fibroids to define a small 3.2 megabase (Mb) commonly deleted region on 7q22.3-q31.1, flanked by clones AC005070 and AC007567. We also used oligonucleotide microarrays to compare the expression profiles of 10 samples of normal myometrium and 15 fibroids, nine of which displayed 7q-deletions. Activating transcription factor 3, patched homolog (Drosophila), homeo box A5, death-associated protein kinase 1, and retinoic acid receptor responder 3 were downregulated, and excision repair crosscomplementing 3, transcription factor AP-2 gamma and protein kinase C beta 1 were upregulated in fibroids. New pathways were discovered related to fibroid formation. The presence or absence of 7q-deletions did not dramatically affect the global expression pattern of the tumours; changes, however, were observed in genes related to vesicular transport and nucleic acid binding.


systematic_name: M265
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE2280
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in the signature set for lymph node metastasis in head and neck squamous cell carcinoma (HNSCC).

description_full:
  Metastasis via the lymphatics is a major risk factor in squamous cell carcinoma of the oral cavity (OSCC). We sought to determine whether the presence of metastasis in the regional lymph node could be predicted by a gene expression signature of the primary tumor. A total of 18 OSCCs were characterized for gene expression by hybridizing RNA to Affymetrix U133A gene chips. Genes with differential expression were identified using a permutation technique and verified by quantitative RT-PCR and immunohistochemistry. A predictive rule was built using a support vector machine, and the accuracy of the rule was evaluated using crossvalidation on the original data set and prediction of an independent set of four patients. Metastatic primary tumors could be differentiated from nonmetastatic primary tumors by a signature gene set of 116 genes. This signature gene set correctly predicted the four independent patients as well as associating five lymph node metastases from the original patient set with the metastatic primary tumor group. We concluded that lymph node metastasis could be predicted by gene expression profiles of primary oral cavity squamous cell carcinomas. The presence of a gene expression signature for lymph node metastasis indicates that clinical testing to assess risk for lymph node metastasis should be possible.


systematic_name: M6311
exact_source: Table 1S
source_species_code: HS
GEO_id: GSE2280
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in the signature set for lymph node metastasis in head and neck squamous cell carcinoma (HNSCC).

description_full:
  Metastasis via the lymphatics is a major risk factor in squamous cell carcinoma of the oral cavity (OSCC). We sought to determine whether the presence of metastasis in the regional lymph node could be predicted by a gene expression signature of the primary tumor. A total of 18 OSCCs were characterized for gene expression by hybridizing RNA to Affymetrix U133A gene chips. Genes with differential expression were identified using a permutation technique and verified by quantitative RT-PCR and immunohistochemistry. A predictive rule was built using a support vector machine, and the accuracy of the rule was evaluated using crossvalidation on the original data set and prediction of an independent set of four patients. Metastatic primary tumors could be differentiated from nonmetastatic primary tumors by a signature gene set of 116 genes. This signature gene set correctly predicted the four independent patients as well as associating five lymph node metastases from the original patient set with the metastatic primary tumor group. We concluded that lymph node metastasis could be predicted by gene expression profiles of primary oral cavity squamous cell carcinomas. The presence of a gene expression signature for lymph node metastasis indicates that clinical testing to assess risk for lymph node metastasis should be possible.


systematic_name: M10336
exact_source: Table 4S: Pgc > 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in epithelial ovarian cancer (EOC) biopsies: invasive (TOV) vs low malignant potential (LMP) tumors.

description_full:
  Tumors of low malignant potential (LMP) represent 20% of epithelial ovarian cancers (EOCs) and are associated with a better prognosis than the invasive tumors (TOV). Defining the relationship between LMPs and TOVs remains an important goal towards understanding the molecular pathways that contribute to prognosis, as well as providing molecular markers, for these EOCs. To this end, DNA microarray analyses were performed either in a primary culture or a tumor tissue model system and selected candidate genes showing a distinctive expression profile between LMPs and TOVs were identified using a class prediction approach based on three statistical methods of analysis. Both model systems appear relevant as candidate genes identified by either model allowed the proper reclassification of samples as either LMPs or TOVs. Selected candidate genes (CAS, CCNE1, LGALS8, ITGbeta3, ATP1B1, FLIP, KRT7 and KRT19) were validated by real-time quantitative PCR analysis and show differential expression between LMPs and TOVs. Immunohistochemistry analyses showed that the two tumor classes were distinguishable by their expression of CAS, TNFR1A, FLIP, CKS1 and CCNE1. These results define signature patterns for gene expression of LMPs and TOVs and identify gene candidates that warrant further study to deepen our understanding of the biology of EOC.


systematic_name: M1595
exact_source: Table 1: Overexpressed genes in patients who developed a recurrence
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in non-neoplastic mucosa samples from colon cancer patients who developed recurrence of the disease.

description_full:
  This study assessed the possibility to build a prognosis predictor, based on microarray gene expression measures, in stage II and III colon cancer patients. Tumour (T) and non-neoplastic mucosa (NM) mRNA samples from 18 patients (nine with a recurrence, nine with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. The k-nearest neighbour method was used for prognosis prediction using T and NM gene expression measures. Six-fold cross-validation was applied to select the number of neighbours and the number of informative genes to include in the predictors. Based on this information, one T-based and one NM-based predictor were proposed and their accuracies were estimated by double cross-validation. In six-fold cross-validation, the lowest numbers of informative genes giving the lowest numbers of false predictions (two out of 18) were 30 and 70 with the T and NM gene expression measures, respectively. A 30-gene T-based predictor and a 70-gene NM-based predictor were then built, with estimated accuracies of 78 and 83%, respectively. This study suggests that one can build an accurate prognosis predictor for stage II and III colon cancer patients, based on gene expression measures, and one can use either tumour or non-neoplastic mucosa for this purpose.


systematic_name: M4671
exact_source: Table 1: Overexpressed genes in patients who remained disease-free
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in non-neoplastic mucosa samples from colon cancer patients who developed recurrence of the disease.

description_full:
  This study assessed the possibility to build a prognosis predictor, based on microarray gene expression measures, in stage II and III colon cancer patients. Tumour (T) and non-neoplastic mucosa (NM) mRNA samples from 18 patients (nine with a recurrence, nine with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. The k-nearest neighbour method was used for prognosis prediction using T and NM gene expression measures. Six-fold cross-validation was applied to select the number of neighbours and the number of informative genes to include in the predictors. Based on this information, one T-based and one NM-based predictor were proposed and their accuracies were estimated by double cross-validation. In six-fold cross-validation, the lowest numbers of informative genes giving the lowest numbers of false predictions (two out of 18) were 30 and 70 with the T and NM gene expression measures, respectively. A 30-gene T-based predictor and a 70-gene NM-based predictor were then built, with estimated accuracies of 78 and 83%, respectively. This study suggests that one can build an accurate prognosis predictor for stage II and III colon cancer patients, based on gene expression measures, and one can use either tumour or non-neoplastic mucosa for this purpose.


systematic_name: M6046
exact_source: Table 2: Overexpressed genes in patients who developed a recurrence
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Up-regulated genes in tumor samples from colon cancer patients who developed recurrence of the disease.

description_full:
  This study assessed the possibility to build a prognosis predictor, based on microarray gene expression measures, in stage II and III colon cancer patients. Tumour (T) and non-neoplastic mucosa (NM) mRNA samples from 18 patients (nine with a recurrence, nine with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. The k-nearest neighbour method was used for prognosis prediction using T and NM gene expression measures. Six-fold cross-validation was applied to select the number of neighbours and the number of informative genes to include in the predictors. Based on this information, one T-based and one NM-based predictor were proposed and their accuracies were estimated by double cross-validation. In six-fold cross-validation, the lowest numbers of informative genes giving the lowest numbers of false predictions (two out of 18) were 30 and 70 with the T and NM gene expression measures, respectively. A 30-gene T-based predictor and a 70-gene NM-based predictor were then built, with estimated accuracies of 78 and 83%, respectively. This study suggests that one can build an accurate prognosis predictor for stage II and III colon cancer patients, based on gene expression measures, and one can use either tumour or non-neoplastic mucosa for this purpose.


systematic_name: M17068
exact_source: Table 2: Overexpressed genes in patients who remained disease-free
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Down-regulated genes in tumor samples from colon cancer patients who developed recurrence of the disease.

description_full:
[cell repeats an earlier one in this file: 1282 characters]


systematic_name: M2837
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in oncocytic follicular carcinoma (FTC) vs mitochondrial-rich papillary carcinoma (PTC) types of thyroid cancer.

description_full:
  The oncogenic pathways in mitochondrial-rich thyroid carcinomas are not clearly understood. To investigate the possible implication of mitochondrial abundance in the genesis of thyroid tumors, we have explored the gene expression profile of six oncocytic carcinomas and six mitochondrial-rich papillary carcinomas using cDNA-microarray technology. A supervised approach allowed us to identify 83 genes differentially expressed in the two types of carcinoma. These genes were classified according to their ontologic profiles. Three genes, NOS3, alpha-actinin-2 and alpha-catenin, suspected of playing a role in tumor genesis, were explored by quantitative RT-PCR analysis and immunohistochemistry. Of the 59 genes overexpressed in papillary carcinomas, 51% were involved in cell communication. Of the 24 genes overexpressed in oncocytic carcinomas, 84% were involved in mitochondrial and cellular metabolism. Our results suggest that mitochondrial respiratory chain complexes III and IV play a significant role in the regulation of reactive oxygen species production by oncocytic tumors.


systematic_name: M15411
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in oncocytic follicular carcinoma (FTC) vs mitochondrial-rich papillary carcinoma (PTC) types of thyroid cancer.

description_full:
  The oncogenic pathways in mitochondrial-rich thyroid carcinomas are not clearly understood. To investigate the possible implication of mitochondrial abundance in the genesis of thyroid tumors, we have explored the gene expression profile of six oncocytic carcinomas and six mitochondrial-rich papillary carcinomas using cDNA-microarray technology. A supervised approach allowed us to identify 83 genes differentially expressed in the two types of carcinoma. These genes were classified according to their ontologic profiles. Three genes, NOS3, alpha-actinin-2 and alpha-catenin, suspected of playing a role in tumor genesis, were explored by quantitative RT-PCR analysis and immunohistochemistry. Of the 59 genes overexpressed in papillary carcinomas, 51% were involved in cell communication. Of the 24 genes overexpressed in oncocytic carcinomas, 84% were involved in mitochondrial and cellular metabolism. Our results suggest that mitochondrial respiratory chain complexes III and IV play a significant role in the regulation of reactive oxygen species production by oncocytic tumors.


description_brief: Candidate genes in the regions of copy number gain in gastric cancer cell lines.
systematic_name: M2212
exact_source: Table 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_full:
  Array-based comparative genomic hybridization (CGH-array) has a powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified a homozygous loss of ADAM23 (2q33.3) in the course of a program to screen a panel of gastric cancer (GC) cell lines (1/32, 3.1%) for genomic copy-number aberrations using our custom-made CGH-array. Infrequent homozygous deletion of ADAM23 was also seen in primary gastric tumors (1/39, 2.6%). ADAM23 mRNA was expressed in normal stomach tissue, but not in the majority of GC cell lines without homozygous deletion of this gene. Expression of ADAM23 mRNA was restored to gene-silenced GC cells after treatment with 5-aza 2'-deoxycytidine. The methylation status of the ADAM23 CpG island, which showed promoter activity, correlated inversely with its expression. Methylation of this CpG island was observed both in GC cell lines and in primary GC tissues; in primary tumors with a hypermethylated CpG island, expression of ADAM23 was lower than in adjacent noncancerous tissues. Moreover, restoration of ADAM23 in GC cells reduced their numbers in colony-formation assays. These results suggest that genetic or epigenetic silencing by hypermethylation of the ADAM23 CpG-rich promoter region leads to loss of ADAM23 function, which may be a factor in gastric carcinogenesis.


systematic_name: M8924
exact_source: Table 1: Fold change > 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in esophageal adenocarcinoma (EAC) and Barret's esophagus (BE) relative to normal esophagi.

description_full:
  To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.


systematic_name: M16944
exact_source: Table 1: Fold change < 1
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in esophageal adenocarcinoma (EAC) and Barret's esophagus (BE) relative to normal esophagi.

description_full:
  To investigate the relationship between Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), we determined gene expression profiles of discrete pathological stages of esophageal neoplasia using a sequence-verified human cDNA microarray. Fifty one RNAs, comprising 24 normal esophagi (NE), 18 BEs, and nine EACs were hybridized to cDNA microarrays. Five statistical analyses were used for the data analysis. Genes showing significantly different expression levels among the three sample groups were identified. Genes were grouped into functional categories based on the Gene Ontology Consortium. Surprisingly, the expression pattern of BE was significantly more similar to EAC than to NE, notwithstanding the known histopathologic differences between BE and EAC. The pattern of NE was clearly distinct from that of EAC. Thirty-six genes were the most differentially modulated, according to these microarray data, in BE-associated neoplastic progression. Twelve genes were significantly differentially expressed in cancer-associated BE's plus EAC (as a single combined tissue group) vs noncancer-associated BE's. These genes represent potential biomarkers to diagnose EAC at its early stages. Our results demonstrate that molecular events at the transcriptional level in BE are remarkably similar to BE's-associated adenocarcinoma of the esophagus. This finding alarmingly implies that BE is biologically closer to cancer than to normal esophagus, and that the cancer risk of BE is perhaps higher than we had imagined. These findings suggest that changes modulated at the molecular biologic level supervene earlier than histologic changes, and that BE is an early intermediate stage in the process of EAC.


systematic_name: M17702
exact_source: Table 1: fold change < 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes genes down-regulated in NT2/D1 cells (embryonal carcinoma) in response to treatment with cisplatin [PubChem=2767].

description_full:
  Testicular germ cell cancers remain one of the few solid tumors routinely cured in advanced stages with conventional cisplatin-based chemotherapy. The mechanisms remain largely unknown. Through use of gene-expression array profiling we define immediate transcriptional targets in response to cisplatin in testicular germ cell-derived human embryonal carcinoma cells. We report 46 genes upregulated and five genes repressed by cisplatin. Several of these gene products, including FAS, TRAILR3, PHLDA3, LRDD, and IER3 are previously implicated in the apoptotic death receptor pathway, while others including SESN1, FDXR, PLK3, and DDIT4 are known mediators of reactive oxygen species generation. Approximately 54% of the upregulated genes are established or suspected downstream targets of p53. Specific siRNA to p53 prevents cisplatin-mediated activation of p53 and p53 pathway genes and renders embryonal carcinoma cells relatively resistant to cisplatin cytotoxicity. Interestingly, in p53 knockdown cells nearly the entire set of identified cisplatin targets fail to respond or have a diminished response to cisplatin, suggesting that many are new direct or indirect targets of p53 including GPR87, STK17A, INPP5D, FLJ11259, and EPS8L2. The data indicate that robust transcriptional activation of p53 is linked to the known hypersensitivity of testicular germ cell tumors to chemotherapy. Many of the gene products may participate in the unique curability of this disease.


systematic_name: M19661
exact_source: Table 3: Fold change > 1
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Candidate progression biomarkers up-regulated in transition from non-tumor-risk associated to tumor-risk associated Barrett's esophagus and then to esophageal adenocarcinoma (EAC).

description_full:
[cell repeats an earlier one in this file: 1712 characters]


systematic_name: M9251
exact_source: Table 1B
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes bound by EWSR1-FLT1 [GeneID=2130;2321] fusion and up-regulated in STA-ET-7.2 cells (Ewing's sarcoma) after knockdown of EWSR1-FLT1 by RNAi.

description_full:
  In all, 85% of Ewing's sarcoma family tumors (ESFT), a neoplasm of unknown histogenesis, express EWS-FLI1 transcription factor gene fusions. To characterize direct target genes avoiding artificial model systems, we cloned genomic DNA from ESFT chromatin precipitating with EWS-FLI1. We now present a comprehensive list of 99 putative transcription factor targets identified, for the first time, by a hypothesis-free approach based on physical interaction. Gene-derived chromatin fragments co-precipitating with EWS-FLI1 were nonrandomly distributed over the human genome and localized predominantly to the upstream region and the first two introns of the genes. At least 20% of putative direct EWS-FLI1 targets were neural genes. One-third of genes recovered showed a significant ESFT-specific expression pattern and were found to be altered upon RNAi-mediated knockdown of EWS-FLI1. Among them, MK-STYX, encoding a MAP kinase phosphatase-like protein, was consistently expressed in ESFT. EWS-FLI1 was found to drive MK-STYX expression by binding to a single ETS binding motif within the first gene intron. MK-STYX serves as precedence for successful recovery of direct EWS-FLI1 targets from the authentic ESFT cellular context, the most relevant system to study oncogenic mechanisms for the discovery of new therapeutic targets in this disease.


systematic_name: M16533
exact_source: Table 1A
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes bound by EWSR1-FLT1 [GeneID=2130;2321] fusion and down-regulated in STA-ET-7.2 cells (Ewing's sarcoma) after knockdown of EWSR1-FLT1 by RNAi.

description_full:
  In all, 85% of Ewing's sarcoma family tumors (ESFT), a neoplasm of unknown histogenesis, express EWS-FLI1 transcription factor gene fusions. To characterize direct target genes avoiding artificial model systems, we cloned genomic DNA from ESFT chromatin precipitating with EWS-FLI1. We now present a comprehensive list of 99 putative transcription factor targets identified, for the first time, by a hypothesis-free approach based on physical interaction. Gene-derived chromatin fragments co-precipitating with EWS-FLI1 were nonrandomly distributed over the human genome and localized predominantly to the upstream region and the first two introns of the genes. At least 20% of putative direct EWS-FLI1 targets were neural genes. One-third of genes recovered showed a significant ESFT-specific expression pattern and were found to be altered upon RNAi-mediated knockdown of EWS-FLI1. Among them, MK-STYX, encoding a MAP kinase phosphatase-like protein, was consistently expressed in ESFT. EWS-FLI1 was found to drive MK-STYX expression by binding to a single ETS binding motif within the first gene intron. MK-STYX serves as precedence for successful recovery of direct EWS-FLI1 targets from the authentic ESFT cellular context, the most relevant system to study oncogenic mechanisms for the discovery of new therapeutic targets in this disease.


systematic_name: M18394
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes in discrete regions of gain within 16q region detected in individual invasive breast cancer tumors.

description_full:
  We analysed chromosome 16q in 106 breast cancers using tiling-path array-comparative genomic hybridization (aCGH). About 80% of ductal cancers (IDCs) and all lobular cancers (ILCs) lost at least part of 16q. Grade I (GI) IDCs and ILCs often lost the whole chromosome arm. Grade II (GII) and grade III (GIII) IDCs showed less frequent whole-arm loss, but often had complex changes, typically small regions of gain together with larger regions of loss. The boundaries of gains/losses tended to cluster, common sites being 54.5-55.5 Mb and 57.4-58.8 Mb. Overall, the peak frequency of loss (83% cancers) occurred at 61.9-62.9 Mb. We also found several 'minimal' regions of loss/gain. However, no mutations in candidate genes (TRADD, CDH5, CDH8 and CDH11) were detected. Cluster analysis based on copy number changes identified a large group of cancers that had lost most of 16q, and two smaller groups (one with few changes, one with a tendency to show copy number gain). Although all morphological types occurred in each cluster group, IDCs (especially GII/GIII) were relatively overrepresented in the smaller groups. Cluster groups were not independently associated with survival. Use of tiling-path aCGH prompted re-evaluation of the hypothetical pathways of breast carcinogenesis. ILCs have the simplest changes on 16q and probably diverge from the IDC lineage close to the stage of 16q loss. Higher-grade IDCs probably develop from low-grade lesions in most cases, but there remains evidence that some GII/GIII IDCs arise without a GI precursor.


systematic_name: M8224
exact_source: Table 2
source_species_code: HS
contributor: Arthur Liberzon
contrib_organization: MSigDB Team
description_brief:
  Genes in discrete regions of loss within 16q region detected in individual invasive breast cancer tumors.

description_full:
  We analysed chromosome 16q in 106 breast cancers using tiling-path array-comparative genomic hybridization (aCGH). About 80% of ductal cancers (IDCs) and all lobular cancers (ILCs) lost at least part of 16q. Grade I (GI) IDCs and ILCs often lost the whole chromosome arm. Grade II (GII) and grade III (GIII) IDCs showed less frequent whole-arm loss, but often had complex changes, typically small regions of gain together with larger regions of loss. The boundaries of gains/losses tended to cluster, common sites being 54.5-55.5 Mb and 57.4-58.8 Mb. Overall, the peak frequency of loss (83% cancers) occurred at 61.9-62.9 Mb. We also found several 'minimal' regions of loss/gain. However, no mutations in candidate genes (TRADD, CDH5, CDH8 and CDH11) were detected. Cluster analysis based on copy number changes identified a large group of cancers that had lost most of 16q, and two smaller groups (one with few changes, one with a tendency to show copy number gain). Although all morphological types occurred in each cluster group, IDCs (especially GII/GIII) were relatively overrepresented in the smaller groups. Cluster groups were not independently associated with survival. Use of tiling-path aCGH prompted re-evaluation of the hypothetical pathways of breast carcinogenesis. ILCs have the simplest changes on 16q and probably diverge from the IDC lineage close to the stage of 16q loss. Higher-grade IDCs probably develop from low-grade lesions in most cases, but there remains evidence that some GII/GIII IDCs arise without a GI precursor.


systematic_name: M14495
exact_source: Table 1: log2 (fold induction) > 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in MDA-MB-231 cells (breast cancer) after knockdown of PRKCA and ETS1 [GeneID=5578;2113] by RNAi.

description_full:
  PKCalpha and Ets1 are both associated with breast cancer progression. Our previous studies suggested that these proteins are likely to functionally interact with one another. Here, we show that attenuation of endogenous PKCalpha expression (siPalpha) by RNA interference leads to reduced Ets1 protein expression in a variety of cancer cells. Pulse-chase experiments and treatment with proteasome inhibitor MG-132 revealed that siPalpha interferes with both Ets1 protein synthesis and stability. The effect of siPalpha on Ets1 expression could be partially prevented by KN-93, suggesting that calcium/calmodulin-dependent kinase II (CaMKII), a modulator of Ets1 activity, may play a role in PKCalpha-dependent Ets1 regulation. In contrast, Ets1-regulating kinases ERK1/2 were not found to be involved in this process. To assess the importance of the PKCalpha/Ets1 interaction, we compared the biological responses of MDA-MB-231 cells to PKCalpha- and Ets1-specific siRNAs (siE1). While only siPalpha induced changes in cellular morphology and anchorage-independent growth, both siRNAs similarly affected cellular responses to the antitumor drug mithramycin A and to UV light. Microarray analyses further showed that the expression of a certain set of genes was equally affected by siPalpha and siE1. The data suggest that Ets1 serves as an effector for PKCalpha to fulfil certain functions in cancer cells.


systematic_name: M2546
exact_source: Table 1-2: siAGF1/siAGF6 > 1
source_species_code: HS
GEO_id: GSE2049
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in Kasumi-1 cells (acute myeloid leukaemia (AML) with the t(8;21) translocation) after knockdown of the AML1 MTG8 fusion [GeneID=861;862] by RNAi.

description_full:
  The chromosomal translocation t(8;21) is associated with 10-15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.


systematic_name: M6469
exact_source: Table 1-2: siAGF1/siAGF6 < 1
source_species_code: HS
GEO_id: GSE2049
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Kasumi-1 cells (acute myeloid leukaemia (AML) with the t(8;21) translocation) after knockdown of the AML1 MTG8 fusion [GeneID=861;862] by RNAi.

description_full:
  The chromosomal translocation t(8;21) is associated with 10-15% of all cases of acute myeloid leukaemia (AML). The resultant fusion protein AML1/MTG8 interferes with haematopoietic gene expression and is an important regulator of leukaemogenesis. We studied the effects of small interfering RNA (siRNA)-mediated AML1/MTG8 depletion on global gene expression in t(8;21)-positive leukaemic cell lines and in primary AML blasts using cDNA arrays, oligonucleotide arrays and real-time reverse transcription-polymerase chain reaction (RT-PCR). Suppression of AML1/MTG8 results in the increased expression of genes associated with myeloid differentiation, such as AZU1, BPI, CTSG, LYZ and RNASE2 as well as of antiproliferative genes such as IGFBP7, MS4A3 and SLA both in blasts and in cell lines. Furthermore, expression levels of several genes affiliated with drug resistance or indicative of poor prognosis AML (BAALC, CD34, PRG2, TSPAN7) are affected by AML1/MTG8 depletion. In conclusion, siRNA-mediated suppression of AML1/MTG8 cause very similar changes in gene expression pattern in t(8;21)-positive cell lines and in primary AML blasts. Furthermore, the results suggest that the specific targeting of AML1/MTG8 function may be a promising approach for complementing existing treatment strategies.


systematic_name: M4381
exact_source: Figure 3: red in PAX8-PPARg(+)
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Top up-regulated genes distinguishing between follicular thyroid carcinoma (FTC) samples by the presence or absence of the PAX8-PPARG [GeneID=7849;5468] fusion protein.

description_full:
  The demonstration of the PAX8-PPAR(gamma) fusion oncogene in a subset of follicular thyroid tumors provides a new and promising starting point to dissect the molecular genetic events involved in the development of this tumor form. In the present study, we compared the gene expression profiles of follicular thyroid carcinomas (FTCs) bearing a PAX8-PPAR(gamma) fusion against FTCs that lack this fusion. Using unsupervised clustering and multidimensional scaling analyses, we show that FTCs possessing a PAX8-PPAR(gamma) fusion have a highly uniform and distinct gene expression signature that clearly distinguishes them from FTCs without the fusion. The PAX8-PPAR(gamma)(+) FTCs grouped in a defined cluster, where highly ranked genes were mostly associated with signal transduction, cell growth and translation control. Notably, a large number of ribosomal protein and translation-associated genes were concurrently underexpressed in the FTCs with the fusion. Taken together, our findings further support that follicular carcinomas with a PAX8-PPAR(gamma) rearrangement constitute a distinct biological entity. The current data represent one step to elucidate the molecular pathways in the development of FTCs with the specific PAX8-PPAR(gamma) fusion.


systematic_name: M836
exact_source: Table 9S: Pgc < 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes up-regulated in pirmary cultures of epithelial ovarian cancer (EOC): invasive (TOV) vs low malignant potential (LMP) tumors.

description_full:
  Tumors of low malignant potential (LMP) represent 20% of epithelial ovarian cancers (EOCs) and are associated with a better prognosis than the invasive tumors (TOV). Defining the relationship between LMPs and TOVs remains an important goal towards understanding the molecular pathways that contribute to prognosis, as well as providing molecular markers, for these EOCs. To this end, DNA microarray analyses were performed either in a primary culture or a tumor tissue model system and selected candidate genes showing a distinctive expression profile between LMPs and TOVs were identified using a class prediction approach based on three statistical methods of analysis. Both model systems appear relevant as candidate genes identified by either model allowed the proper reclassification of samples as either LMPs or TOVs. Selected candidate genes (CAS, CCNE1, LGALS8, ITGbeta3, ATP1B1, FLIP, KRT7 and KRT19) were validated by real-time quantitative PCR analysis and show differential expression between LMPs and TOVs. Immunohistochemistry analyses showed that the two tumor classes were distinguishable by their expression of CAS, TNFR1A, FLIP, CKS1 and CCNE1. These results define signature patterns for gene expression of LMPs and TOVs and identify gene candidates that warrant further study to deepen our understanding of the biology of EOC.


systematic_name: M13220
exact_source: Table 9S: Pgc > 0
source_species_code: HS
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in pirmary cultures of epithelial ovarian cancer (EOC): invasive (TOV) vs low malignant potential (LMP) tumors.

description_full:
  Tumors of low malignant potential (LMP) represent 20% of epithelial ovarian cancers (EOCs) and are associated with a better prognosis than the invasive tumors (TOV). Defining the relationship between LMPs and TOVs remains an important goal towards understanding the molecular pathways that contribute to prognosis, as well as providing molecular markers, for these EOCs. To this end, DNA microarray analyses were performed either in a primary culture or a tumor tissue model system and selected candidate genes showing a distinctive expression profile between LMPs and TOVs were identified using a class prediction approach based on three statistical methods of analysis. Both model systems appear relevant as candidate genes identified by either model allowed the proper reclassification of samples as either LMPs or TOVs. Selected candidate genes (CAS, CCNE1, LGALS8, ITGbeta3, ATP1B1, FLIP, KRT7 and KRT19) were validated by real-time quantitative PCR analysis and show differential expression between LMPs and TOVs. Immunohistochemistry analyses showed that the two tumor classes were distinguishable by their expression of CAS, TNFR1A, FLIP, CKS1 and CCNE1. These results define signature patterns for gene expression of LMPs and TOVs and identify gene candidates that warrant further study to deepen our understanding of the biology of EOC.


description_brief: Genes up-regulated in Tet-On HEK293 cells (embryonic kidney) by expression of HNF4A [GeneID=3172].
systematic_name: M11410
exact_source: Table 1: fold change > 1
source_species_code: HS
GEO_id: GSE2700
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_full:
  Hepatocyte nuclear factor 4alpha (HNF4alpha) is a tissue-specific transcription factor known to regulate a large number of genes in hepatocytes and pancreatic beta cells. Although HNF4alpha is highly expressed in some sections of the kidney, little is known about its role in this organ and about HNF4alpha-regulated genes in the kidney cells. The abundance and activity of HNF4alpha are frequently reduced in renal cell carcinoma (RCC) indicating some tumor suppressing function of HNF4alpha in renal cells. To determine the potential role of HNF4alpha in RCC, we used Flp recombinase-mediated gene integration to generate human embryonic kidney cells (HEK293) that conditionally express wild-type or mutated HNF4alpha. Expression of wild-type HNF4alpha but not of the mutants led to reduction of proliferation and alterations of cell morphology. These effects were reversible and induced at physiological concentrations of HNF4alpha. Using gene expression profiling by microarrays, we determined genes regulated by HNF4alpha. Interestingly, many of the genes regulated by HNF4alpha have been shown to be deregulated in RCC microarray studies. These genes (ACY1, WT1, SELENBP1, COBL, EFHD1, AGXT2L1, ALDH5A1, THEM2, ABCB1, FLJ14146, CSPG2, TRIM9 and HEY1) are good candidates for genes whose activity is changed upon the decrease of HNF4alpha in RCC.


systematic_name: M10457
exact_source: Table 1: fold change < 1
source_species_code: HS
GEO_id: GSE2700
contributor: Leona Saunders
contrib_organization: MSigDB Team
description_brief:
  Genes down-regulated in Tet-On HEK293 cells (embryonic kidney) by expression of HNF4A [GeneID=3172].

description_full:
  Hepatocyte nuclear factor 4alpha (HNF4alpha) is a tissue-specific transcription factor known to regulate a large number of genes in hepatocytes and pancreatic beta cells. Although HNF4alpha is highly expressed in some sections of the kidney, little is known about its role in this organ and about HNF4alpha-regulated genes in the kidney cells. The abundance and activity of HNF4alpha are frequently reduced in renal cell carcinoma (RCC) indicating some tumor suppressing function of HNF4alpha in renal cells. To determine the potential role of HNF4alpha in RCC, we used Flp recombinase-mediated gene integration to generate human embryonic kidney cells (HEK293) that conditionally express wild-type or mutated HNF4alpha. Expression of wild-type HNF4alpha but not of the mutants led to reduction of proliferation and alterations of cell morphology. These effects were reversible and induced at physiological concentrations of HNF4alpha. Using gene expression profiling by microarrays, we determined genes regulated by HNF4alpha. Interestingly, many of the genes regulated by HNF4alpha have been shown to be deregulated in RCC microarray studies. These genes (ACY1, WT1, SELENBP1, COBL, EFHD1, AGXT2L1, ALDH5A1, THEM2, ABCB1, FLJ14146, CSPG2, TRIM9 and HEY1) are good candidates for genes whose activity is changed upon the decrease of HNF4alpha in RCC.


