Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

Lecarpentier J1, Silvestri V1, Kuchenbaecker KB1, Barrowdale D1, Dennis J1, McGuffog L1, Soucy P1, Leslie G1, Rizzolo P1, Navazio AS1, Valentini V1, Zelli V1, Lee A1, Amin Al Olama A1, Tyrer JP1, Southey M1, John EM1, Conner TA1, Goldgar DE1, Buys SS1, Janavicius R1, Steele L1, Ding YC1, Neuhausen SL1, Hansen TVO1, Osorio A1, Weitzel JN1, Toss A1, Medici V1, Cortesi L1, Zanna I1, Palli D1, Radice P1, Manoukian S1, Peissel B1, Azzollini J1, Viel A1, Cini G1, Damante G1, Tommasi S1, Peterlongo P1, Fostira F1, Hamann U1, Evans DG1, Henderson A1, Brewer C1, Eccles D1, Cook J1, Ong KR1, Walker L1, Side LE1, Porteous ME1, Davidson R1, Hodgson S1, Frost D1, Adlard J1, Izatt L1, Eeles R1, Ellis S1, Tischkowitz M1; EMBRACE, Godwin AK1, Meindl A1, Gehrig A1, Dworniczak B1, Sutter C1, Engel C1, Niederacher D1, Steinemann D1, Hahnen E1, Hauke J1, Rhiem K1, Kast K1, Arnold N1, Ditsch N1, Wang-Gohrke S1, Wappenschmidt B1, Wand D1, Lasset C1, Stoppa-Lyonnet D1, Belotti M1, Damiola F1, Barjhoux L1, Mazoyer S1; GEMO Study Collaborators, Van Heetvelde M1, Poppe B1, De Leeneer K1, Claes KBM1, de la Hoya M1, Garcia-Barberan V1, Caldes T1, Perez Segura P1, Kiiski JI1, Aittomäki K1, Khan S1, Nevanlinna H1, van Asperen CJ1; HEBON, Vaszko T1, Kasler M1, Olah E1, Balmaña J1, Gutiérrez-Enríquez S1, Diez O1, Teulé A1, Izquierdo A1, Darder E1, Brunet J1, Del Valle J1, Feliubadalo L1, Pujana MA1, Lazaro C1, Arason A1, Agnarsson BA1, Johannsson OT1, Barkardottir RB1, Alducci E1, Tognazzo S1, Montagna M1, Teixeira MR1, Pinto P1, Spurdle AB1, Holland H1; KConFab Investigators, Lee JW1, Lee MH1, Lee J1, Kim SW1, Kang E1, Kim Z1, Sharma P1, Rebbeck TR1, Vijai J1, Robson M1, Lincoln A1, Musinsky J1, Gaddam P1, Tan YY1, Berger A1, Singer CF1, Loud JT1, Greene MH1, Mulligan AM1, Glendon G1, Andrulis IL1, Toland AE1, Senter L1, Bojesen A1, Nielsen HR1, Skytte AB1, Sunde L1, Jensen UB1, Pedersen IS1, Krogh L1, Kruse TA1, Caligo MA1, Yoon SY1, Teo SH1, von Wachenfeldt A1, Huo D1, Nielsen SM1, Olopade OI1, Nathanson KL1, Domchek SM1, Lorenchick C1, Jankowitz RC1, Campbell I1, James P1, Mitchell G1, Orr N1, Park SK1, Thomassen M1, Offit K1, Couch FJ1, Simard J1, Easton DF1, Chenevix-Trench G1, Schmutzler RK1, Antoniou AC1, Ottini L1.

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Abstract

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.