Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non–Muscle-Invasive Bladder Cancer

Abstract

Purpose: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied. Experimental Design: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed. Results: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts (12% [12/99] vs. 8.7% [10/115], p=0.4). In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, p=0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response (DDR) genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in NMIBC patients not receiving BCG, P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG. Conclusions: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of the initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.

Effects of Nursing Care for the Treatment of Patients with Bladder Cancer: A Systematic Review and Meta-analysis

“…(13). In 2014, there were about 78100 new cases of bladder cancer in China, with a standardized incidence rate of 3.61/100000, about 32100 deaths, and a standardized mortality rate of 1.30/100000 [ 23 ]. Despite China has lower bladder cancer rates and fatality rates than the rest of the globe, it still shows an increasing trend in the past decade, and has become one of the important disease burdens in China [ 24 ].…”

“…. In 2014, there were about 78100 new cases of bladder cancer in China, with a standardized incidence rate of 3.61/ 100000, about 32100 deaths, and a standardized mortality rate of 1.30/100000[23]. Despite China has lower bladder…”

Increased stromal densities of B cells, CD103+ cells, and CD163+ M2-like macrophages associate with poor clinical outcomes in BCG treated non-muscle invasive bladder cancer

“…Constitutive expression of PD-L1 on cancer cells could result from mutations in DNA damage repair genes or could be induced via the phenomenon of adaptive immune resistance during disease progression [39]. While the mutational profiles of tumors used in our study were not available, previous studies have reported an enrichment of DNA damage repair gene mutations in high-grade NMIBC tumors [40, 41].…”

Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog and NIPAL1

“…Finally, we note that the study of iUC in canine populations may fill in gaps in studies of bladder cancer in humans. The numerous cohorts amassed for studies of human bladder cancer risk feature, on average, > 80% males and 80–85% non-muscle invasive disease 68 – 71 , even though muscle invasive bladder cancer carries a much higher risk of early mortality 72 . Women are underrepresented in these studies because they are less likely to get bladder cancer than men, however they more often get invasive disease and their relative survival expectancy is reduced by five percentage points or more across all stages of the disease ( https://seer.cancer.gov/ ).…”