Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores
Authors: Lecarpentier Julie , Silvestri Valentina , Kuchenbaecker Karoline B. , Barrowdale Daniel , Dennis Joe , McGuffog Lesley , Soucy Penny , Leslie Goska , Rizzolo Piera , Navazio Anna Sara , Valentini Virginia , Zelli Veronica , Lee Andrew , Amin Al Olama Ali , Tyrer Jonathan P. , Southey Melissa , John Esther M. , Conner Thomas A. , Goldgar David E. , Buys Saundra S. , Janavicius Ramunas , Steele Linda , Ding Yuan Chun , Neuhausen Susan L. , Hansen Thomas V.O. , Osorio Ana , Weitzel Jeffrey N. , Toss Angela , Medici Veronica , Cortesi Laura , Zanna Ines , Palli Domenico , Radice Paolo , Manoukian Siranoush , Peissel Bernard , Azzollini Jacopo , Viel Alessandra , Cini Giulia , Damante Giuseppe , Tommasi Stefania , Peterlongo Paolo , Fostira Florentia , Hamann Ute , Evans D. Gareth , Henderson Alex , Brewer Carole , Eccles Diana , Cook Jackie , Ong Kai-ren , Walker Lisa , Side Lucy E. , Porteous Mary E. , Davidson Rosemarie , Hodgson Shirley , Frost Debra , Adlard Julian , Izatt Louise , Eeles Ros , Ellis Steve , Tischkowitz Marc ,   EMBRACE, Godwin Andrew K. , Meindl Alfons , Gehrig Andrea , Dworniczak Bernd , Sutter Christian , Engel Christoph , Niederacher Dieter , Steinemann Doris , Hahnen Eric , Hauke Jan , Rhiem Kerstin , Kast Karin , Arnold Norbert , Ditsch Nina , Wang-Gohrke Shan , Wappenschmidt Barbara , Wand Dorothea , Lasset Christine , Stoppa-Lyonnet Dominique , Belotti Muriel , Damiola Francesca , Barjhoux Laure , Mazoyer Sylvie ,   GEMO Study Collaborators, Van Heetvelde Mattias , Poppe Bruce , De Leeneer Kim , Claes Kathleen B.M. , de la Hoya Miguel , Garcia-Barberan Vanesa , Caldes Trinidad , Perez Segura Pedro , Kiiski Johanna I. , Aittomäki Kristiina , Khan Sofia , Nevanlinna Heli , van Asperen Christi J. ,   HEBON, Vaszko Tibor , Kasler Miklos , Olah Edith , Balmaña Judith , Gutiérrez-Enríquez Sara , Diez Orland , Teulé Alex , Izquierdo Angel , Darder Esther , Brunet Joan , Del Valle Jesús , Feliubadalo Lidia , Pujana Miquel Angel , Lazaro Conxi , Arason Adalgeir , Agnarsson Bjarni A. , Johannsson Oskar Th. , Barkardottir Rosa B. , Alducci Elisa , Tognazzo Silvia , Montagna Marco , Teixeira Manuel R. , Pinto Pedro , Spurdle Amanda B. , Holland Helene ,   KConFab Investigators, Lee Jong Won , Lee Min Hyuk , Lee Jihyoun , Kim Sung-Won , Kang Eunyoung , Kim Zisun , Sharma Priyanka , Rebbeck Timothy R. , Vijai Joseph , Robson Mark , Lincoln Anne , Musinsky Jacob , Gaddam Pragna , Tan Yen Y. , Berger Andreas , Singer Christian F. , Loud Jennifer T. , Greene Mark H. , Mulligan Anna Marie , Glendon Gord , Andrulis Irene L. , Toland Amanda Ewart , Senter Leigha , Bojesen Anders , Nielsen Henriette Roed , Skytte Anne-Bine , Sunde Lone , Jensen Uffe Birk , Pedersen Inge Sokilde , Krogh Lotte , Kruse Torben A. , Caligo Maria A. , Yoon Sook-Yee , Teo Soo-Hwang , von Wachenfeldt Anna , Huo Dezheng , Nielsen Sarah M. , Olopade Olufunmilayo I. , Nathanson Katherine L. , Domchek Susan M. , Lorenchick Christa , Jankowitz Rachel C. , Campbell Ian , James Paul , Mitchell Gillian , Orr Nick , Park Sue Kyung , Thomassen Mads , Offit Kenneth , Couch Fergus J. , Simard Jacques , Easton Douglas F. , Chenevix-Trench Georgia , Schmutzler Rita K. , Antoniou Antonis C. , Ottini Laura 
Published: April 2017

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.