Table 3

Gene sets associated with response (R) and progressive disease (PD)

Gene set*Description*All studies, raw fdrTrial 039
Bortezomib, raw npvDex, raw npv
Associated with R†     
    BRENTANI_CELL_ADHESION‡ Cancer-related genes involved in cell adhesion and metalloproteinases 0.046 0.0373 NC 
    MYELIN_DOWN_LE‡ Genes down-regulated in Egr2Lo/Lo mice (mutations in the transcription factor Egr2) with expression altered after sciatic nerve injury 0.057 0.0047 0.1446 
    PASSERINI_ADHESION‡ Genes associated with cellular adhesion that are differentially expressed in endothelial cells of pig aortas from regions of disturbed flow 0.088 0.0657 0.5820 
    cytokinePathway‡ Intercellular signaling in the immune system occurs via secretion of cytokines, which promote antigen-dependent B- and T-cell response 0.093 0.0149 NC 
    KRAS_TOP100_KNOCKDOWN_CORDERO‡ Genes up-regulated in K-ras knockdown vs control in a human cell line 0.103 0.0722 0.3936 
    MOUSE_DENA_UP‡ Genes up-regulated in hepatoma induced by diethylnitrosamine 0.105 0.0684 NC 
    ST_MYOCYTE_AD_PATHWAY‡ Cardiac myocytes have a variety of adrenergic receptors that induce subtype-specific signaling effects 0.108 0.0209 0.0618 
    MYC_293_DOWN‡ Genes down-regulated by MYC in 293T (transformed fetal renal cell) 0.163 0.0401 0.4203 
    ST_ADRENERGIC‡ Adrenergic receptors respond to epinephrine and norepinephrine signaling 0.175 0.3021 0.2914 
    HYPOXIA_UP_MANALO‡ Genes up-regulated in human pulmonary endothelial cells under hypoxic conditions or after exposure to AdCA5 (constitutively active HIF-1α) 0.186 0.1941 0.6324 
    lairPathway‡ The local acute inflammatory response is mediated by activated macrophages and mast cells or by complement activation 0.188 0.0860 NC 
    NFKB_UP_HINATA‡ Genes up-regulated by NF-κB 0.201 0.0794 0.2811 
    Smooth_muscle_contraction‡ NA 0.227 0.0124 NC 
    Striated_muscle_contraction‡ NA 0.233 0.0108 0.3853 
    TNFA_HEPATO_UP Genes up-regulated by TNFA in Hc cells (normal hepatocyte) 0.084 0.6158 0.7953 
    RAS_STROMA_DOWN_CROONQUIST Genes down-regulated in multiple myeloma cells with N-ras-activating mutations versus those cocultured with bone marrow stromal cells 0.096 0.0804 NC 
    IL6_STROMA_UP_CROONQUIST Genes up-regulated in multiple myeloma cells exposed to the pro-proliferative cytokine IL-6 versus those cocultured with bone marrow stromal cells 0.099 0.1527 0.7804 
    MOUSE_CIP_UP Genes up-regulated in hepatoma induced by ciprofibrate 0.100 0.0608 NC 
    Statin_Pathway_PharmGKB NA 0.159 0.0451 0.9095 
    BRENTANI_CYTOSKELETON Cancer-related genes also related to the cytoskeleton 0.185 0.0409 0.6597 
Associated with PD§     
    Translation_Factors‡ NA 0.048 0.0294 NC 
    Ribosomal_Proteins‡ NA 0.111 0.0115 NC 
    ELECTRON_TRANSPORT_CHAIN Genes involved in electron transport 0.109 0.3554 0.6618 
    VOXPHOS Oxidative phosphorylation 0.118 0.3116 0.6303 
    Electron_Transport_Chain NA 0.118 0.3535 0.6561 
    MRNA_PROCESSING Genes involved in mRNA processing 0.126 0.0916 0.0713 
    Oxidative phosphorylation NA 0.157 0.4757 0.9730 
    MRNA SPLICING Genes involved in mRNA splicing 0.166 0.1780 0.0247 
    RNA_transcription_Reactome NA 0.202 0.2380 0.0351 
    mRNA processing NA 0.207 0.0978 0.0137 
    IFNG_5ENDOTHELIAL_DOWN Genes down-regulated by interferon-γ in colon, dermal, iliac, aortic, and lung endothelial cells 0.212 0.2767 0.4042 
    MITOCHONDRIA Mitochondrial genes 0.216 0.5342 0.3284 
    HUMAN_MITODB_6_2002 Mitochondrial genes 0.217 0.5601 0.3699 
    eif2Pathway Eukaryotic initiation factor 2 (EIF2) initiates translation by transferring Met-tRNA to the 40S ribosome in a GTP-dependent process 0.219 0.8587 NC 
    GOLDRATH_HP Genes up-regulated in CD8+ T cells undergoing homeostatic proliferation (HP) versus naive CD8+ T-cell populations; these genes are not up-regulated versus effector or memory cell population 0.224 0.1534 0.5239 
    CELL_CYCLE_REGULATOR Obsolete by GO; was not defined before being made obsolete 0.226 0.0596 0.1615 
Gene set*Description*All studies, raw fdrTrial 039
Bortezomib, raw npvDex, raw npv
Associated with R†     
    BRENTANI_CELL_ADHESION‡ Cancer-related genes involved in cell adhesion and metalloproteinases 0.046 0.0373 NC 
    MYELIN_DOWN_LE‡ Genes down-regulated in Egr2Lo/Lo mice (mutations in the transcription factor Egr2) with expression altered after sciatic nerve injury 0.057 0.0047 0.1446 
    PASSERINI_ADHESION‡ Genes associated with cellular adhesion that are differentially expressed in endothelial cells of pig aortas from regions of disturbed flow 0.088 0.0657 0.5820 
    cytokinePathway‡ Intercellular signaling in the immune system occurs via secretion of cytokines, which promote antigen-dependent B- and T-cell response 0.093 0.0149 NC 
    KRAS_TOP100_KNOCKDOWN_CORDERO‡ Genes up-regulated in K-ras knockdown vs control in a human cell line 0.103 0.0722 0.3936 
    MOUSE_DENA_UP‡ Genes up-regulated in hepatoma induced by diethylnitrosamine 0.105 0.0684 NC 
    ST_MYOCYTE_AD_PATHWAY‡ Cardiac myocytes have a variety of adrenergic receptors that induce subtype-specific signaling effects 0.108 0.0209 0.0618 
    MYC_293_DOWN‡ Genes down-regulated by MYC in 293T (transformed fetal renal cell) 0.163 0.0401 0.4203 
    ST_ADRENERGIC‡ Adrenergic receptors respond to epinephrine and norepinephrine signaling 0.175 0.3021 0.2914 
    HYPOXIA_UP_MANALO‡ Genes up-regulated in human pulmonary endothelial cells under hypoxic conditions or after exposure to AdCA5 (constitutively active HIF-1α) 0.186 0.1941 0.6324 
    lairPathway‡ The local acute inflammatory response is mediated by activated macrophages and mast cells or by complement activation 0.188 0.0860 NC 
    NFKB_UP_HINATA‡ Genes up-regulated by NF-κB 0.201 0.0794 0.2811 
    Smooth_muscle_contraction‡ NA 0.227 0.0124 NC 
    Striated_muscle_contraction‡ NA 0.233 0.0108 0.3853 
    TNFA_HEPATO_UP Genes up-regulated by TNFA in Hc cells (normal hepatocyte) 0.084 0.6158 0.7953 
    RAS_STROMA_DOWN_CROONQUIST Genes down-regulated in multiple myeloma cells with N-ras-activating mutations versus those cocultured with bone marrow stromal cells 0.096 0.0804 NC 
    IL6_STROMA_UP_CROONQUIST Genes up-regulated in multiple myeloma cells exposed to the pro-proliferative cytokine IL-6 versus those cocultured with bone marrow stromal cells 0.099 0.1527 0.7804 
    MOUSE_CIP_UP Genes up-regulated in hepatoma induced by ciprofibrate 0.100 0.0608 NC 
    Statin_Pathway_PharmGKB NA 0.159 0.0451 0.9095 
    BRENTANI_CYTOSKELETON Cancer-related genes also related to the cytoskeleton 0.185 0.0409 0.6597 
Associated with PD§     
    Translation_Factors‡ NA 0.048 0.0294 NC 
    Ribosomal_Proteins‡ NA 0.111 0.0115 NC 
    ELECTRON_TRANSPORT_CHAIN Genes involved in electron transport 0.109 0.3554 0.6618 
    VOXPHOS Oxidative phosphorylation 0.118 0.3116 0.6303 
    Electron_Transport_Chain NA 0.118 0.3535 0.6561 
    MRNA_PROCESSING Genes involved in mRNA processing 0.126 0.0916 0.0713 
    Oxidative phosphorylation NA 0.157 0.4757 0.9730 
    MRNA SPLICING Genes involved in mRNA splicing 0.166 0.1780 0.0247 
    RNA_transcription_Reactome NA 0.202 0.2380 0.0351 
    mRNA processing NA 0.207 0.0978 0.0137 
    IFNG_5ENDOTHELIAL_DOWN Genes down-regulated by interferon-γ in colon, dermal, iliac, aortic, and lung endothelial cells 0.212 0.2767 0.4042 
    MITOCHONDRIA Mitochondrial genes 0.216 0.5342 0.3284 
    HUMAN_MITODB_6_2002 Mitochondrial genes 0.217 0.5601 0.3699 
    eif2Pathway Eukaryotic initiation factor 2 (EIF2) initiates translation by transferring Met-tRNA to the 40S ribosome in a GTP-dependent process 0.219 0.8587 NC 
    GOLDRATH_HP Genes up-regulated in CD8+ T cells undergoing homeostatic proliferation (HP) versus naive CD8+ T-cell populations; these genes are not up-regulated versus effector or memory cell population 0.224 0.1534 0.5239 
    CELL_CYCLE_REGULATOR Obsolete by GO; was not defined before being made obsolete 0.226 0.0596 0.1615 

Top-scoring gene sets from GSEA analysis of the full set of bortezomib samples are shown, along with corresponding FDR statistical scores. The nominal P values for the 2 arms of the 039 trial, used to assess the extent to which the gene set associations were treatment specific, are also shown.

NA indicates no description available; NC, no correlation with phenotype.

*

Gene set name and description from Molecular Signature Database.39 

†

Top 20 gene sets are listed.

‡

Gene sets showing generally consistent phenotype association based on analysis of individual trials are shown in ranked order.

§

All 16 gene sets are listed.

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