Hu Dong Gui, Mackenzie Peter I, Nair Pramod C, McKinnon Ross A, Meech Robyn
Department of Clinical Pharmacology and Flinders Cancer Centre, Flinders University, College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, Adelaide 5042, SA, Australia.
Cancers (Basel). 2020 Nov 13;12(11):3369. doi: 10.3390/cancers12113369.
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 (, ), KIRC (, ), PAAD (); sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (), BRCA (), COAD (), HNSC (), KIRC (, , , ), KIRP (), LIHC (, , , , ), LUAD (), LUSC (), PAAD (), SARC (), and SKCM (). 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.
药物代谢动力学（ADME）基因是一组参与药物吸收、分布、代谢和排泄（ADME）的基因。肿瘤内ADME基因的表达谱被认为会影响癌症患者的生存；然而，这一点尚未得到系统研究。在本研究中，我们对来自癌症基因组图谱（TCGA）的泛癌数据集进行了全面分析，揭示了21种不同癌症类型中ADME基因的肿瘤内差异表达谱。大多数基因在癌症特异性患者队列中也表现出较高的个体间变异性。使用Kaplan-Meier曲线和对数秩检验，我们发现32个核心ADME基因中有20个的肿瘤内表达水平与这些癌症的总生存期（OS）相关。在这些基因中，有5个在三种癌症中与不良OS显著相关，包括皮肤黑色素瘤（SKCM）、肾透明细胞癌（KIRC）、胰腺腺癌（PAAD）；16个在12种癌症中与良好OS显著相关，包括膀胱癌（BLCA）、乳腺癌（BRCA）、结肠癌（COAD）、头颈部鳞状细胞癌（HNSC）、肾透明细胞癌（KIRC）、肾乳头状细胞癌（KIRP）、肝癌（LIHC）、肺腺癌（LUAD）、肺鳞状细胞癌（LUSC）、胰腺腺癌（PAAD）、肉瘤（SARC）和皮肤黑色素瘤（SKCM）。总体而言，这些数据提供了令人信服的证据，支持ADME基因作为预后生物标志物和潜在治疗靶点。我们提出，ADME基因的肿瘤内表达可能通过多种机制影响癌症患者的生存，这些机制可能包括代谢/转运抗癌药物、激活抗癌药物，以及代谢/转运多种参与为癌细胞提供代谢燃料和/或控制促生长信号通路的内源性分子。
