The Expression Profiles of ADME Genes in Human Cancers and Their Associations with Clinical Outcomes

SIMPLE SUMMARY: There are roughly 300 genes that are classically defined as ADME genes based on their roles in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes in human cancers and their impact on cancer patient survival remain to be systematically assessed. Our pan-cancer gene expression analysis revealed that about half of all ADME genes were expressed in all 21 cancers assessed. Most genes showed highly variable expression within and among different cancers. Our pan-cancer survival analysis identified a set of core ADME genes whose intratumoral expression was associated with overall survival in these cancers. These findings highlight the potential implication of ADME genes as cancer prognostic biomarkers and therapeutic targets. We propose that intratumoral expression of ADME genes can influence cancer patient survival through not only drug metabolism and disposition, but also metabolism and disposition of numerous endogenous molecules that can fuel and/or stimulate cancer growth. ABSTRACT: ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival; however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral expression profiles for ADME genes in 21 different cancer types. Most genes also showed high interindividual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1), LUAD (SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.