Germline homologous recombination repair (gHRR) variants in bladder cancer: Preliminary evidence and clinical implications

Objective: The contribution of germline DNA repair gene (gDRG) variants to bladder cancer (BC) susceptibility and progression is still poorly defined, particularly in European populations. This study aims to evaluate the prevalence and clinical implications of germline homologous recombination repair (HRR) gene variants in BC patients of European ancestry. Methods: In this prospective case-control study, 75 BC patients attending follow-up at a single tertiary centre were screened for germline variants in 20 gDRGs. Patients were included regardless of disease stage and classified by pathogenicity (Class 3-5). Clinical characteristics and outcomes were compared between variant-positive and variant-negative patients. Results: Among 75 eligible patients, 72 underwent successful germline sequencing. A total of 23 patients (30.6%) harboured at least one pathogenic, likely pathogenic, or VUS variant. The most frequently altered genes included ATM (n = 6), ATR (n = 4), BARD1 (n = 4), CHEK2 (n = 3) and PMS2 (n = 3). Eight patients (34.7%) had multiple variants, and one carried three variants. Notably, 25.8% of NMIBC and 50% of MIBC patients had gDRG variants. Moreover, 30% of patients with low-grade G1 disease harboured at least one variant. Patients with gDRG variants had a higher rate of histopathological variants (34.8% vs. 13.5%) and underwent radical cystectomy at a younger age (60 vs. 75 years, p < 0.05). Conclusions: Germline HRR variants are prevalent in BC patients and may influence disease aggressiveness and treatment decisions. These findings support broader implementation of germline testing in BC and warrant further validation in larger cohorts.