TP63 isoform expression is linked with distinct clinical outcomes in cancer
TP63 isoform expression is linked with distinct clinical outcomes in cancer
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DOI：
10.1016/j.ebiom.2019.11.022
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发表时间：
2020-01-01
期刊：
影响因子：
11.1
通讯作者：
Palmbos, Phillip L.
中科院分区：
文献类型：
--
作者：
Bankhead, Armand, III;McMaster, Thomas;Palmbos, Phillip L.
背景：一半的肌肉浸润性膀胱癌患者会复发并伴有转移性疾病，需要分子检测来预测复发。TP63已被提出作为膀胱癌的预后生物标志物，但与临床结果相关的报道相互矛盾。由于TP63以多种异构体表达，我们假设这些与临床结果的冲突关联可以通过TP63不同异构体表达的截然相反的作用来解释。方法：利用来自癌症基因组图谱（TCGA）的RNA-Seq数据，对来自29种疾病的8,519例患者的TP63亚型水平表达进行量化，并将其与临床协变量（如生存期、分期）相关联。利用基因注释数据库和膀胱癌患者的新发现，建立了一个完整的TP63亚型目录。使用定量RT-PCR和单独的膀胱癌队列验证定量和未注释的TP63亚型。结果：DNp63亚型表达与改善膀胱腔亚型患者生存率相关（HR = 0.89, CI 0.80-0.99, Cox p = 0.034）。相反，在基础亚型患者中，TAp63亚型表达与膀胱癌患者生存率降低相关（HR = 2.35, CI 1.64-3.37, Cox p < 0.0001）。在多个TCGA疾病队列中观察到这些关联，并与表皮分化（DNp63）和免疫相关（TAp63）基因特征相关。解释：这些结果全面定义了TP63异构体在人类癌症中的表达，并表明TP63异构体参与了不同的转录程序，对临床结果有相反的影响。(C) 2019作者。Elsevier B.V.出版
Background: Half of muscle-invasive bladder cancer patients will relapse with metastatic disease and molecular tests to predict relapse are needed. TP63 has been proposed as a prognostic biomarker in bladder cancer, but reports associating it with clinical outcomes are conflicting. Since TP63 is expressed as multiple isoforms, we hypothesized that these conflicting associations with clinical outcome may be explained by distinct opposing effects of differential TP63 isoform expression.Methods: Using RNA-Seq data from The Cancer Genome Atlas (TCGA), TP63 isoform-level expression was quantified and associated with clinical covariates (e.g. survival, stage) across 8,519 patients from 29 diseases. A comprehensive catalog of TP63 isoforms was assembled using gene annotation databases and de novo discovery in bladder cancer patients. Quantifications and un-annotated TP63 isoforms were validated using quantitative RT-PCR and a separate bladder cancer cohort.Findings: DNp63 isoform expression was associated with improved bladder cancer patient survival in patients with a luminal subtype (HR = 0.89, CI 0.80-0.99, Cox p = 0.034). Conversely, TAp63 isoform expression was associated with reduced bladder cancer patient survival in patients with a basal subtype (HR = 2.35, CI 1.64-3.37, Cox p < 0.0001). These associations were observed in multiple TCGA disease cohorts and correlated with epidermal differentiation (DNp63) and immune-related (TAp63) gene signatures.Interpretation: These results comprehensively define TP63 isoform expression in human cancer and suggest that TP63 isoforms are involved in distinct transcriptional programs with opposing effects on clinical outcome. (C) 2019 The Authors. Published by Elsevier B.V.