Integrative Genomic Stratification of DNA Damage Repair–Associated Molecular Subtypes and Prognostic Modeling in Bladder Cancer

Abstract

Bladder cancer is characterized by substantial molecular heterogeneity that complicates prognostic assessment and therapeutic decision-making. DNA damage repair (DDR) pathways play a central role in maintaining genomic stability, yet a comprehensive genomics-based stratification framework centered on DDR alterations remains insufficiently defined. In this study, we performed an integrative genomic analysis of 406 bladder cancer samples from The Cancer Genome Atlas. Weighted gene coexpression network analysis was applied to identify bladder cancer–relevant DDR modules from a curated DDR gene set. Protein–protein interaction analysis prioritized 44 core DDR genes for molecular classification. Unsupervised consensus clustering revealed two DDR-associated molecular subtypes with significantly distinct overall survival and transcriptional programs. One subtype exhibited enrichment of immune-related pathways and stromal signatures, whereas the other was characterized by enhanced cell-cycle progression and DNA replication activity. To enable individualized prognostic prediction, an eight-gene DDR-associated signature was constructed using the least absolute shrinkage and selection operator and multivariable Cox regression analyses. The model effectively stratified patients into high- and low-risk groups and demonstrated stable predictive performance, with 1-, 3-, and 5-year area under the curve values of 0.745, 0.736, and 0.754, respectively. The signature was further evaluated in an independent GEO cohort (GSE13507), in which DDR-based clustering and risk stratification showed consistent prognostic trends, supporting the generalizability of the framework. High-risk tumors displayed increased tumor mutational burden, distinct immune infiltration patterns, and differential predicted drug sensitivity profiles. Protein-level validation supported dysregulated expression of key genes in tumor tissues. Collectively, this integrative genomics study establishes a DDR-centered molecular classification and prognostic framework, providing insights into genomic instability–driven heterogeneity and potential strategies for precision stratification in bladder cancer.