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.
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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jul 14 [Epub ahead of print]
Eugene J Pietzak, Karissa Whiting, Preethi Srinivasan, Chaitanya Bandlamudi, Aliya Khurram, Vijai Joseph, Aleksandra Walasek, Emily Bochner, Timothy Clinton, Nima Almassi, Hong Truong, Manuel R de Jesus Escano, Michal Wiseman, Diana Mandelker, Yelena Kemel, Liying Zhang, Michael F Walsh, Karen A Cadoo, Jonathan A Coleman, Hikmat Al-Ahmadie, Jonathan E Rosenberg, Gopakumar V Iyer, David B Solit, Irina Ostrovnaya, Kenneth Offit, Mark E Robson, Zsofia K Stadler, Michael F Berger, Dean F Bajorin, Maria Carlo, Bernard H Bochner
Memorial Sloan Kettering Cancer Center, New York, NY, United States., Memorial Sloan Kettering Cancer Center, San Carlos, CA, United States., Cleveland Clinic, Cleveland, OH, United States., University of California, Los Angeles, Los Angeles, CA, United States., St. James's Hospital, Trinity College Dublin, Trinity St. James's Cancer Institute, Dublin 8, Ireland., Memorial Sloan Kettering Cancer Center, NY, NY, United States., Memorial Sloan Kettering Cancer Center, New York, New York, United States., Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, United States.