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.

中文翻译：

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TP63亚型的表达与癌症的独特临床结局有关。

背景技术一半的肌肉浸润性膀胱癌患者将因转移性疾病而复发，因此需要分子测试来预测复发。TP63已被提议作为膀胱癌的预后生物标志物，但有关将其与临床结果相关的报道相互矛盾。由于TP63被表达为多种同工型，我们假设这些与临床结果的冲突关联可能是由差异TP63同工型表达的明显相反作用所解释的。方法利用来自癌症基因组图谱（TCGA）的RNA-Seq数据，对TP63亚型水平的表达进行了定量，并与29种疾病的8,519例患者的临床协变量（例如生存期，分期）相关。使用基因注释数据库和从头发现在膀胱癌患者中收集了TP63亚型的全面目录。定量和未注释的TP63亚型使用定量RT-PCR和单独的膀胱癌队列进行了验证。结论DNp63亚型的表达与管腔亚型患者的膀胱癌患者生存期改善有关（HR = 0.89，CI 0.80-0.99，Cox p = 0.034）。相反，在具有基础亚型的患者中，TAp63亚型的表达与膀胱癌患者生存期降低有关（HR = 2.35，CI 1.64-3.37，Cox p <0.0001）。这些关联在多个TCGA疾病队列中观察到，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人类癌症中TP63异构体的表达，并表明TP63异构体参与不同的转录程序，对临床结果产生相反的影响。