The Expression Profiles Of ADME Genes In Human Cancers And ...

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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.

Keywords: cancer; drug absorption; drug distribution; drug excretion; drug metabolism; endobiotic metabolism; overall survival; prognostic biomarker; therapeutic target.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Kaplan-Meier survival analysis and logrank…

Figure 1

Kaplan-Meier survival analysis and logrank test show significant associations of intratumoral expression levels…

Figure 1 Kaplan-Meier survival analysis and logrank test show significant associations of intratumoral expression levels of core ADME (absorption, distribution, metabolism, and excretion) genes coding for phase I drug-metabolizing enzymes with overall survival rates in TCGA cancers. For Kaplan-Meier survival analysis, the patients were separated into high-expression group (upper 50 percentile, red curve) and low-expression group (lower 50 percentile, blue curve) by gene expression levels in each TCGA cancer type as indicated. The number of patients in each group was given in bracket following the p-value. A Bonferroni-corrected cutoff logrank p-value of < 0.05 indicates statistical significance.
Figure 2

Figure 2

Kaplan-Meier survival analysis and Logrank…

Figure 2

Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral expression levels…

Figure 2 Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral expression levels of dihydropyrimidine dehydrogenase (DPYD) in skin cancer SKCM (stratified by tumor type) (A), CYP2D6 in breast cancer BRCA (stratified by tumor stage) (B), and UGT2B15 in bladder cancer (stratified by sex) (C) with overall survival rates. For Kaplan-Meier survival analysis, the patients were separated into high-expression group (upper 50 percentile, red curve) and low-expression group (lower 50 percentile, blue curve) by gene expression levels in each TCGA cancer type as indicated. The number of patients in each group was given in bracket following the p-value. A Bonferroni-corrected cutoff logrank p-value of < 0.05 indicates statistical significance.
Figure 3

Figure 3

Kaplan-Meier survival analysis and Logrank…

Figure 3

Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral expression levels…

Figure 3 Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral expression levels of core ADME genes coding for phase II drug-metabolizing enzymes with overall survival rates in TCGA cancers. For Kaplan-Meier survival analysis, the patients were separated into high-expression group (upper 50 percentile, red curve) and low-expression group (lower 50 percentile, blue curve) by gene expression levels in each TCGA cancer type as indicated. The number of patients in each group was given in bracket following the p-value. A Bonferroni-corrected cutoff logrank p-value of < 0.05 indicates statistical significance.
Figure 4

Figure 4

Kaplan-Meier survival analysis and Logrank…

Figure 4

Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral expression levels…

Figure 4 Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral expression levels of core ADME genes coding for ABC (A) and SLC (B) drug transporters with overall survival rates in TCGA cancers. For Kaplan-Meier survival analysis, the patients were separated into high-expression group (upper 50 percentile, red curve) and low-expression group (lower 50 percentile, blue curve) by gene expression levels in each TCGA cancer type as indicated. The number of patients in each group was given in bracket following the p-value. A Bonferroni-corrected cutoff logrank p-value of < 0.05 indicates statistical significance.
Figure 5

Figure 5

Kaplan-Meier survival analysis and Logrank…

Figure 5

Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral SLC15A2 expression…

Figure 5 Kaplan-Meier survival analysis and Logrank test show significant associations of intratumoral SLC15A2 expression levels with overall survival rates in the lung cancer cohort from the Kaplan-Meier Plotter (KM-LUAD). Survival analysis was conducted using the expression data from the two SLC15A2 probe sets: 205316_at (A) and 205317_s_at (B). Patients were analysed altogether or following stratification by tumor histology. For analysis, the patients were separated using Median expression into high-expression group (Red curve) and low-expression group (Black curve). The number of patients in each group was given in bracket following the p-value. A Bonferroni-corrected cutoff logrank p-value of < 0.05 indicates statistical significance. Hazard ratio (HR) and 95% confidence interval (CI) (bracket) are also provided.
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