TP53 disruptive mutation predicts platinum‐based chemotherapy and PD‐1 / PD‐L1 blockade response in urothelial carcinoma

作者：Kaifeng Jin, Jingtong Xu, Jingtong Xu, Xiaohe Su, Ziyue Xu, Bingyu Li, Ge Liu, Hailong Liu, Yiwei Wang, Yu Zhu, Le Xu, Weijuan Zhang, Zhaopei Liu, Zewei Wang, Yuan Chang, Jiejie Xu, Jiejie Xu · 发表于：The Journal of Pathology · 年份：2024 · DOI：10.1002/path.6266 · 被引用次数：13 · 研究领域：Bladder and Urothelial Cancer Treatments、Cancer Immunotherapy and Biomarkers、Urinary and Genital Oncology Studies

Abstract TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co‐occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53 Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53 Nondisruptive mutations and those with wild‐type TP53 . Significantly, patients with TP53 Disruptive mutations exhibit an increased probability of responding favorably to PD‐1/PD‐L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53 Disruptive mutations showed an enriched APOBEC‐ and POLE‐related mutational signature, as ...