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 TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive 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 TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
TP53突变是尿路上皮癌（UrCa）中最常见的遗传改变之一，TP53突变体的异质性导致异质性的临床结果。这项研究旨在探讨UrCa中特定TP53突变的临床相关性。在这项研究中,共纳入8个队列，以及匹配的临床注释。根据p53蛋白功能和结构的紊乱程度，TP53突变分为破坏性和非破坏性。我们在本地数据集和公开数据集中评估了TP53突变的临床意义。UrCa中TP53突变的共同发生事件，以及他们的治疗适应症，功能效应，和肿瘤免疫微环境，也被调查了。在49.7%的UrCa患者中发现TP53突变。在这个群体中,25.1%的患者携带TP53破坏性突变，与TP53非破坏性突变个体和TP53野生型个体相比,遗传改变与显著较差的总生存期(OS)相关。重要的是,TP53颠覆性突变的患者对PD-1/PD-L1阻断和化学免疫疗法反应良好的概率增加.同时,在接受化疗的TP53突变状态不同的患者中,OS没有显著差异.具有TP53破坏性突变的样品显示出富集的APOBEC和POLE相关的突变特征，以及升高的肿瘤突变负担。携带TP53破坏性突变的肿瘤对免疫疗法的敏感性可能归因于炎症的肿瘤微环境，其特征是CD8T细胞浸润和干扰素-γ信号激活增加。总之,具有TP53破坏性突变的UrCa患者的生存率降低，但他们可能对PD-1/PD-L1阻断治疗和化学免疫疗法反应良好.通过区分特定的TP53突变，我们可以改善风险分层,并为UrCa患者提供个性化的基因组学指导治疗.©2024作者由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
