Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
Authors: Patel Vivek L. , Busch Evan L. , Friebel Tara M. , Cronin Angel , Leslie Goska , McGuffog Lesley , Adlard Julian , Agata Simona , Agnarsson Bjarni A. , Ahmed Munaza , Aittomäki Kristiina , Alducci Elisa , Andrulis Irene L. , Arason Adalgeir , Arnold Norbert , Artioli Grazia , Arver Brita , Auber Bernd , Azzollini Jacopo , Balmaña Judith , Barkardottir Rosa B. , Barnes Daniel R. , Barroso Alicia , Barrowdale Daniel , Belotti Muriel , Benitez Javier , Bertelsen Birgitte , Blok Marinus J. , Bodrogi Istvan , Bonadona Valérie , Bonanni Bernardo , Bondavalli Davide , Boonen Susanne E. , Borde Julika , Borg Ake , Bradbury Angela R. , Brady Angela , Brewer Carole , Brunet Joan , Buecher Bruno , Buys Saundra S. , Cabezas-Camarero Santiago , Caldés Trinidad , Caliebe Almuth , Caligo Maria A. , Calvello Mariarosaria , Campbell Ian G. , Carnevali Ileana , Carrasco Estela , Chan Tsun L. , Chu Annie T.W. , Chung Wendy K. , Claes Kathleen B.M. , Collaborators GEMO Study , Collaborators EMBRACE , Cook Jackie , Cortesi Laura , Couch Fergus J. , Daly Mary B. , Damante Giuseppe , Darder Esther , Davidson Rosemarie , de la Hoya Miguel , Puppa Lara Della , Dennis Joe , Díez Orland , Ding Yuan Chun , Ditsch Nina , Domchek Susan M. , Donaldson Alan , Dworniczak Bernd , Easton Douglas F. , Eccles Diana M. , Eeles Rosalind A. , Ehrencrona Hans , Ejlertsen Bent , Engel Christoph , Evans D. Gareth , Faivre Laurence , Faust Ulrike , Feliubadaló Lídia , Foretova Lenka , Fostira Florentia , Fountzilas George , Frost Debra , García-Barberán Vanesa , Garre Pilar , Gauthier-Villars Marion , Géczi Lajos , Gehrig Andrea , Gerdes Anne-Marie , Gesta Paul , Giannini Giuseppe , Glendon Gord , Godwin Andrew K. , Goldgar David E. , Greene Mark H. , Gutierrez-Barrera Angelica M. , Hahnen Eric , Hamann Ute , Hauke Jan , Herold Natalie , Hogervorst Frans B.L. , Honisch Ellen , Hopper John L. , Hulick Peter J. , Investigators KConFab , Investigators HEBON , Izatt Louise , Jager Agnes , James Paul , Janavicius Ramunas , Jensen Uffe Birk , Jensen Thomas Dyrso , Johannsson Oskar Th. , John Esther M. , Joseph Vijai , Kang Eunyoung , Kast Karin , Kiiski Johanna I. , Kim Sung-Won , Kim Zisun , Ko Kwang-Pil , Konstantopoulou Irene , Kramer Gero , Krogh Lotte , Kruse Torben A. , Kwong Ava , Larsen Mirjam , Lasset Christine , Lautrup Charlotte , Lazaro Conxi , Lee Jihyoun , Lee Jong Won , Lee Min Hyuk , Lemke Johannes , Lesueur Fabienne , Liljegren Annelie , Lindblom Annika , Llovet Patricia , Lopez-Fernández Adria , Lopez-Perolio Irene , Lorca Victor , Loud Jennifer T. , Ma Edmond S.K. , Mai Phuong L. , Manoukian Siranoush , Mari Veronique , Martin Lynn , Matricardi Laura , Mebirouk Noura , Medici Veronica , Meijers-Heijboer Hanne E.J. , Meindl Alfons , Mensenkamp Arjen R. , Miller Clare , Gomes Denise Molina , Montagna Marco , Mooij Thea M. , Moserle Lidia , Mouret-Fourme Emmanuelle , Mulligan Anna Marie , Nathanson Katherine L. , Navratilova Marie , Nevanlinna Heli , Niederacher Dieter , Nielsen Finn C. Cilius , Nikitina-Zake Liene , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Ong Kai-Ren , Osorio Ana , Ott Claus-Eric , Palli Domenico , Park Sue K. , Parsons Michael T. , Pedersen Inge Sokilde , Peissel Bernard , Peixoto Ana , Pérez-Segura Pedro , Peterlongo Paolo , Petersen Annabeth Høgh , Porteous Mary E. , Pujana Miguel Angel , Radice Paolo , Ramser Juliane , Rantala Johanna , Rashid Muhammad U. , Rhiem Kerstin , Rizzolo Piera , Robson Mark E. , Rookus Matti A. , Rossing Caroline M. , Ruddy Kathryn J. , Santos Catarina , Saule Claire , Scarpitta Rosa , Schmutzler Rita K. , Schuster Hélène , Senter Leigha , Seynaeve Caroline M. , Shah Payal D. , Sharma Priyanka , Shin Vivian Y. , Silvestri Valentina , Simard Jacques , Singer Christian F. , Skytte Anne-Bine , Snape Katie , Solano Angela R. , Soucy Penny , Southey Melissa C. , Spurdle Amanda B. , Steele Linda , Steinemann Doris , Stoppa-Lyonnet Dominique , Stradella Agostina , Sunde Lone , Sutter Christian , Tan Yen Y. , Teixeira Manuel R. , Teo Soo Hwang , Thomassen Mads , Tibiletti Maria Grazia , Tischkowitz Marc , Tognazzo Silvia , Toland Amanda E. , Tommasi Stefania , Torres Diana , Toss Angela , Trainer Alison H. , Tung Nadine , van Asperen Christi J. , van der Baan Frederieke H. , van der Kolk Lizet E. , van der Luijt Rob B. , van Hest Liselotte P. , Varesco Liliana , Varon-Mateeva Raymonda , Viel Alessandra , Vierstraete Jeroen , Villa Roberta , von Wachenfeldt Anna , Wagner Philipp , Wang-Gohrke Shan , Wappenschmidt Barbara , Weitzel Jeffrey N. , Wieme Greet , Yadav Siddhartha , Yannoukakos Drakoulis , Yoon Sook-Yee , Zanzottera Cristina , Zorn Kristin K. , D'Amico Anthony V. , Freedman Matthew L. , Pomerantz Mark M. , Chenevix-Trench Georgia , Antoniou Antonis C. , Neuhausen Susan L. , Ottini Laura , Nielsen Henriette Roed , Rebbeck Timothy R. 
Published: November 2019

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer.

Significance:
Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.