Cancer Susceptibility Mutations in Patients With Urothelial Malignancies

Author:

Carlo Maria I.1,Ravichandran Vignesh1,Srinavasan Preethi1,Bandlamudi Chaitanya1,Kemel Yelena1,Ceyhan-Birsoy Ozge1,Mukherjee Semanti1,Mandelker Diana1,Chaim Joshua1,Knezevic Andrea1,Rana Satshil1,Fnu Zarina1,Breen Kelsey1,Arnold Angela G.1,Khurram Aliya1,Tkachuk Kaitlyn1,Cipolla Catharine K.1,Regazzi Ashley1,Hakimi A. Ari1,Al-Ahmadie Hikmat1,Dalbagni Guido1,Cadoo Karen A.1,Walsh Michael F.1,Teo Min-Yuen1,Funt Samuel A.1,Coleman Jonathan A.1,Bochner Bernard H.1,Iyer Gopa1,Solit David B.1,Stadler Zsofia K.1,Zhang Liying1,Rosenberg Jonathan E.1,Taylor Barry S.1,Robson Mark E.1,Berger Michael F.1,Vijai Joseph1,Bajorin Dean F.1,Offit Kenneth1

Affiliation:

1. Memorial Sloan Kettering Cancer Center, New York, NY

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.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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