Tumor mutational burden to predict overall survival independent of TP53 status in TCGA bladder cancer cohort.

Abstract

833 Background: Tumor mutational burden (TMB) is an emerging biomarker in bladder cancer and is linked to response to immune checkpoint inhibitors. However, its association with survival in untreated TCGA populations and its interaction with TP53 mutation status remain under-investigated in nontrial, publicly available cohorts. We evaluated the prognostic value of TMB and TP53 mutations in The Cancer Genome Atlas (TCGA) bladder urothelial carcinoma (BLCA) dataset. Methods: Publicly available TCGA-BLCA PanCanAtlas (2018) data were obtained via cBioPortal. Tumor mutational burden (TMB, mutations/Mb) was derived from sample level nonsynonymous mutation counts. High TMB was defined using the standard clinical threshold (≥10 mut/Mb) and a cohort-specific median cutoff (5.8 mut/Mb). TP53 mutation status was extracted from the mutation annotation file (MAF). Overall survival time and status were obtained from patient level clinical data. Cox proportional hazards models adjusted for age and sex were used, and Kaplan–Meier curves generated for visualization. Variant histology and stage were excluded due to limited availability in this dataset. Results: A total of 408 patients were included after excluding missing survival/predictor data, with 180 deaths observed. High TMB (≥10 mut/Mb) was significantly associated with improved overall survival (HR 0.60, 95% CI 0.41- 0.89; p = 0.011). Using a median-based cutoff, high TMB remained associated with improved survival (HR 0.56, 95% CI 0.41- 0.77; p < 0.001). TP53 mutation was not independently associated with survival (HR 1.0, p > 0.5), and no significant interaction between TP53 and TMB was observed (p > 0.90). Age was an independent risk factor (HR 1.03 per year, p < 0.001), while sex was not significant. Conclusions: In TCGA BLCA, high tumor mutational burden is independently associated with improved overall survival, regardless of TP53 mutation status. TP53 does not modify the prognostic effect of TMB. These findings support TMB as a robust prognostic marker even outside immunotherapy treated populations and warrant validation in clinical cohorts.