학술논문
Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer
Document Type
article
Author
Pietzak, Eugene J; Whiting, Karissa; Srinivasan, Preethi; Bandlamudi, Chaitanya; Khurram, Aliya; Joseph, Vijai; Walasek, Aleksandra; Bochner, Emily; Clinton, Timothy; Almassi, Nima; Truong, Hong; de Jesus Escano, Manuel R; Wiseman, Michal; Mandelker, Diana; Kemel, Yelena; Zhang, Liying; Walsh, Michael F; Cadoo, Karen A; Coleman, Jonathan A; Al-Ahmadie, Hikmat; Rosenberg, Jonathan E; Iyer, Gopakumar V; Solit, David B; Ostrovnaya, Irina; Offit, Kenneth; Robson, Mark E; Stadler, Zsofia K; Berger, Michael F; Bajorin, Dean F; Carlo, Maria; Bochner, Bernard H
Source
Clinical Cancer Research. 28(19)
Subject
Language
Abstract
PurposeIdentification 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 designGermline 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.ResultsA 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 genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma.ConclusionsOur results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.