ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research Topicp53 in Cancer Therapy: The Impact of Mutations on the Genome GuardianView all 6 articles
Effect of co-occurring mutations in TP53 gene and TERT promoter on the survival of bladder cancer patients
Provisionally accepted
- 1Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
- 2Universita degli Studi della Campania Luigi Vanvitelli, Caserta, Italy
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Background: Mutations in the TP53 gene and telomerase reverse transcriptase promoter (TERTp) are among the most frequent genetic alterations in bladder cancer, but the clinical impact of their co-occurrence has not been fully explored. In this study, we assessed the mutational landscape as well as the prognostic significance of concurrent TP53 and TERTp mutations in a cohort of bladder urothelial carcinoma patients. Methods: Using data from the cBioPortal database, we retrospectively analysed primary bladder urothelial carcinoma cases profiled with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assays. We investigated the relationships between tumour mutational burden (TMB), microsatellite instability (MSI), and somatic mutations. The Kaplan-Meier method was used to calculate patient overall survival. Log-rank testing and multivariable Cox proportional hazards modelling were used to evaluate prognostic factors. Results: Among the 1,111 cancer cases, 416 exhibited concurrent mutations in both TERTp and TP53, 387 harboured mutations exclusively in TERTp, 132 showed mutations only in the TP53 gene, and 176 cases were double wild-type for both genetic regions (wt/wt). Overall survival was significantly longer in the wt/wt group compared to TERTp (HR 1.83, 95% CI 1.27 - 2.62, P<0.001), to TP53 mutant alone (HR 1.84, 95% CI 1.19 - 2.85, P=0.006) and to TERTp/TP53 (HR 2.32, 95% CI 1.63 – 3.31, P<0.001) mutant groups. The presence of TP53 and TERTp mutations was associated with higher tumour mutational burden (TMB ≥10 mutations/Mb) and increased microsatellite instability (MSI) scores (P < 0.001). The significant association between TERTp and TP53 mutations was independently validated in a separate cohort. Conclusions: Bladder urothelial cancer can be stratified into biologically and clinically distinct subtypes on the basis of cancer driver mutations, with concomitant TERTp/TP53 nucleotide changes strongly linked to reduced patients' overall survival. These results suggest a potential cooperative interaction between mutant TERTp and TP53 in the pathogenesis of bladder cancer, highlighting their significance as prognostic biomarkers and promising targets for novel therapeutic strategies.
Keywords: Bladder urothelial carcinoma, co-mutations, Telomerase, TERT promoter mutations, TP53 mutations
Received: 19 Dec 2025; Accepted: 16 Feb 2026.
Copyright: © 2026 Tornesello, Piccirillo, Tambaro and Simeon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Maria Lina Tornesello
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