# Effect of co-occurring mutations in TP53 gene and TERT promoter on the survival of bladder cancer patients

## TL;DR

Bladder cancer patients with mutations in both TP53 and TERT promoter have significantly worse survival, suggesting these mutations act together to worsen outcomes.

## Contribution

This study identifies a strong prognostic link between co-occurring TP53 and TERTp mutations in bladder cancer patients.

## Key findings

- Patients with both TP53 and TERTp mutations had the worst overall survival compared to other mutation groups.
- Co-occurring TP53 and TERTp mutations were associated with higher tumor mutational burden and microsatellite instability.
- The association was validated in an independent cohort, supporting the biological relevance of these mutations.

## Abstract

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 TERTp and TP53 mutations in a cohort of bladder urothelial carcinoma patients.

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.

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 TERTp and TP53 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.

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.