Cancer Susceptibility Mutations in Patients With Urothelial Malignancies.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Carlo Maria I, Ravichandran Vignesh, Srinavasan Preethi, Bandlamudi Chaitanya, Kemel Yelena, Ceyhan-Birsoy Ozge, Mukherjee Semanti, Mandelker Diana, Chaim Joshua, Knezevic Andrea, Rana Satshil, Fnu Zarina, Breen Kelsey, Arnold Angela G, Khurram Aliya, Tkachuk Kaitlyn, Cipolla Catharine K, Regazzi Ashley, Hakimi A Ari, Al-Ahmadie Hikmat, Dalbagni Guido, Cadoo Karen A, Walsh Michael F, Teo Min-Yuen, Funt Samuel A, Coleman Jonathan A, Bochner Bernard H, Iyer Gopa, Solit David B, Stadler Zsofia K, Zhang Liying, Rosenberg Jonathan E, Taylor Barry S, Robson Mark E, Berger Michael F, Vijai Joseph, Bajorin Dean F, Offit Kenneth
Аннотация
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.