Synapse - Cancer susceptibility mutations in patients with urothelial malignancies

Cancer susceptibility mutations in patients with urothelial malignancies Journal Article

Authors:	Carlo, M. I.; Ravichandran, V.; Srinavasan, P.; Bandlamudi, C.; Kemel, Y.; Ceyhan-Birsoy, O.; Mukherjee, S.; Mandelker, D.; Chaim, J.; Knezevic, A.; Rana, S.; Fnu, Z.; Breen, K.; Arnold, A. G.; Khurram, A.; Tkachuk, K.; Cipolla, C. K.; Regazzi, A.; Hakimi, A. A.; Al-Ahmadie, H.; Dalbagni, G.; Cadoo, K. A.; Walsh, M. F.; Teo, M. Y.; Funt, S. A.; Coleman, J. A.; Bochner, B. H.; Iyer, G.; Solit, D. B.; Stadler, Z. K.; Zhang, L.; Rosenberg, J. E.; Taylor, B. S.; Robson, M. E.; Berger, M. F.; Vijai, J.; Bajorin, D. F.; Offit, K.
Article Title:	Cancer susceptibility mutations in patients with urothelial malignancies
Abstract:	PURPOSE: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
Journal Title:	Journal of Clinical Oncology
Volume:	38
Issue:	5
ISSN:	0732-183X
Publisher:	American Society of Clinical Oncology
Date Published:	2020-02-10
Start Page:	406
End Page:	414
Language:	English
DOI:	10.1200/jco.19.01395
PUBMED:	31794323
PROVIDER:	scopus
PMCID:	PMC7351337
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85078082219&doi=10.1200%2fJCO.19.01395&partnerID=40&md5=6bdcb6cabc353848c55ffff45b587f5a
Notes:	Article -- Author Preethi Srinivasan's last name is misspelled on the original publication -- Authors Fnu (Shameer) Zarina and Vijai Joseph's first and last names are reversed on the original publication -- Export Date: 2 March 2020 -- Source: Scopus