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This study aimed to investigate the clinical relevance of specific <jats:italic>TP53<\/jats:italic> mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. <jats:italic>TP53<\/jats:italic> 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 <jats:italic>TP53<\/jats:italic> mutations in our local datasets and publicly available datasets. The co\u2010occurring events of <jats:italic>TP53<\/jats:italic> mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. <jats:italic>TP53<\/jats:italic> mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried <jats:italic>TP53<\/jats:italic><jats:sup>Disruptive<\/jats:sup> mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with <jats:italic>TP53<\/jats:italic><jats:sup>Nondisruptive<\/jats:sup> mutations and those with wild\u2010type <jats:italic>TP53<\/jats:italic>. Significantly, patients with <jats:italic>TP53<\/jats:italic><jats:sup>Disruptive<\/jats:sup> mutations exhibit an increased probability of responding favorably to PD\u20101\/PD\u2010L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying <jats:italic>TP53<\/jats:italic> mutation status who underwent chemotherapy. Samples with <jats:italic>TP53<\/jats:italic><jats:sup>Disruptive<\/jats:sup> mutations showed an enriched APOBEC\u2010 and POLE\u2010related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying <jats:italic>TP53<\/jats:italic><jats:sup>Disruptive<\/jats:sup> mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8<jats:sup>+<\/jats:sup>T cell infiltration and interferon\u2010gamma signaling activation. In conclusion, UrCa patients with <jats:italic>TP53<\/jats:italic><jats:sup>Disruptive<\/jats:sup> mutations have shown reduced survival rates, yet they may respond well to PD\u20101\/PD\u2010L1 blockade therapy and chemoimmunotherapy. By distinguishing specific <jats:italic>TP53<\/jats:italic> mutations, we can improve risk stratification and offer personalized genomics\u2010guided therapy to UrCa patients. \u00a9 2024 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6266","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T05:22:13Z","timestamp":1708492933000},"page":"139-149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp><i>TP53<\/i><\/scp> disruptive mutation predicts platinum\u2010based chemotherapy and <scp>PD\u20101<\/scp>\/<scp>PD\u2010L1<\/scp> blockade response in urothelial carcinoma"],"prefix":"10.1002","volume":"263","author":[{"given":"Kaifeng","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Urology, Zhongshan 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