Synapse - Inherited germline cancer susceptibility gene variants in individuals with non-muscle-invasive bladder cancer

Inherited germline cancer susceptibility gene variants in individuals with non-muscle-invasive bladder cancer Journal Article

Authors:	Pietzak, E. J.; Whiting, K.; Srinivasan, P.; Bandlamudi, C.; Khurram, A.; Joseph, V.; Walasek, A.; Bochner, E.; Clinton, T.; Almassi, N.; Truong, H.; de Jesus Escano, M. R.; Wiseman, M.; Mandelker, D.; Kemel, Y.; Zhang, L.; Walsh, M. F.; Cadoo, K. A.; Coleman, J. A.; Al-Ahmadie, H.; Rosenberg, J. E.; Iyer, G. V.; Solit, D. B.; Ostrovnaya, I.; Offit, K.; Robson, M. E.; Stadler, Z. K.; Berger, M. F.; Bajorin, D. F.; Carlo, M.; Bochner, B. H.
Article Title:	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. Patho-genic 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 genes, most within the nucleotide excision repair (ERCC2/3) and homologous recom-bination 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 asso-ciated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma.Conclusions: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regard-less of initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.
Keywords:	mortality; chemotherapy; recurrence; risk; survivors; guidelines; urothelial cancer; repair; mutations; sensitivity
Journal Title:	Clinical Cancer Research
Volume:	28
Issue:	19
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2022-10-01
Start Page:	4267
End Page:	4277
Language:	English
ACCESSION:	WOS:000886369700001
DOI:	10.1158/1078-0432.Ccr-22-1006
PROVIDER:	wos
PMCID:	PMC9527498
PUBMED:	35833951
Notes:	Article -- Source: Wos