Cancer screening, prevention, and therapy can be made more specific to each individual with the help of knowledge about inherited germline variations. Patients with locally advanced or metastatic urothelial carcinoma often carry pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes, but the prevalence and significance of these variants in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is poorly understood. Tumor and normal tissue sequencing data from 2 separate groups of patients initially diagnosed with NMIBC were subjected to a germline study. Clinicopathologic characteristics and clinical outcomes were correlated with P/LP germline variations in more than or equal to 76 genes known to increase the risk of developing cancer in a family. P/LP germline mutations were found at a similar rate in both of the NMIBC cohorts, at 12% (12/99) and 8.7% (10/115), respectively (P=0.4). Patients with high-grade NMIBC were the only ones in the combined study to have P/LP germline mutations (22/163), while none of the 46 patients with low-grade NMIBC did (13.5% vs. 0%, P=0.005). The majority of P/LP variations in DNA damage response genes were found in the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways, affecting 15 (9.2%) patients with high-grade NMIBC. P/LP germline variations were not related to worse recurrence-free or progression-free survival in individuals treated with Bacillus Calmette-Guerin BCG, or with risk of developing upper tract urothelial carcinoma, in contrast to previous results in patients with NMIBC not receiving BCG. Based on researchers’ findings, it is reasonable to provide germline counseling and testing to all individuals with high-grade bladder cancer, irrespective of the stage at which their tumor was first diagnosed. Patients with high-grade NMIBC may benefit from therapeutic approaches that target poor DNA repair.
