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

$\textbf{Purpose}$ $\textit{BRCA1/2}$ mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of $\textit{BRCA1/2}$ 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 $\textit{BRCA1/2}$ mutations and implications for cancer risk prediction. $\textbf{Materials and Methods}$ We genotyped 1,802 male carriers of $\textit{BRCA1/2}$ mutations from the Consortium of Investigators of Modifiers of $\textit{BRCA1/2}$ 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 $\textit{BRCA1/2}$ mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. $\textbf{Results}$ In male carriers of $\textit{BRCA1/2}$ 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 $\textit{BRCA1}$ mutations and from 19% to 61% for carriers of $\textit{BRCA2}$ mutations, respectively. $\textbf{Conclusion}$ PRSs may provide informative cancer risk stratification for male carriers of $\textit{BRCA1/2}$ 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.Supported by the Italian Association for Cancer Research [AIRC, IG16933; for genotyping of the OncoArray in male mutation carriers]; genotyping of the OncoArray in CIMBA was supported by the Ministere de l`Économie, Innovation et Exportation du Québec Grant No. PSR-SIIRI-701 and the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l`Économie, de la Science et de l´Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH; Grant No. 1U19-CA148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer [DRIVE] project; Grant No. X01-HG007492 to the Centre for Inherited Disease Research), Cancer Research UK (C1287/A16563), Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control, Ministry of Health and Welfare (Republic of Korea) (1420190), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia), and German Cancer Aid (110837); CIMBA data management and data analysis were supported by Cancer Research UK Grants No. C12292/A20861 and C12292/A11174. A.C.A. is a Cancer Research UK Senior Cancer Research Fellow; G.C.-T. is an NHMRC Senior Principal Research Fellow; J.L. has been financially supported by the Fondation ARC Grant No. SAE20131200623; the PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l`Économie, de la Science et de l´Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation. Also supported by the Ministere de l`Économie, Innovation et Exportation du Québec Grant No. PSR-SIIRI-701. The Breast Cancer Family Registry (BCFR) was supported by Grant No. UM1-CA164920 from the National Cancer Institute. BFBOCC-LT (Baltic Familial Breast Ovarian Cancer Consortium Lithuanian section) was supported by Lithuania Research Council of Lithuania (Grant No. SEN-18/2015). BRICOH (Beckman Research Institute of the City of Hope) S.L.N. is partially supported by the Morris and Horowitz Families Professorship. CNIO (Spanish National Cancer Centre) was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA), and SAF2010-20493. A.O. is supported by Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R. The City of Hope Clinical Cancer Genomics Community Research Network (COH-CCGCRN) was supported in part by Grant No. RC4CA153828 (principal investigator, J.W.) from the National Cancer Institute and the Office of the Director, NIH. The CONSIT team was supported by the Italian Association of Cancer Research to P.P. (IG12821), P.R. (IG15547), and L.O. (IG16933), and from Italian citizens who allocated the 5 x 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5x1000”) to S.M. Supported by Sapienza University of Rome (post-doc annual research grant “Avvio alla ricerca” 2016) to V.S. Supported by the ITT (Istituto Toscano Tumori) triennal grant 2010 to D.P. DEMOKRITOS was supported by the European Union (European Social Fund) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. The DKFZ study was supported by the DKFZ. EMBRACE was supported by Cancer Research UK Grants No. C1287/A10118 and C1287/A11990. D.G.E. is supported by an NIH Research (NIHR) grant to the Biomedical Research Centre, Manchester. The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. R.E. is supported by Cancer Research UK Grant No. C5047/A8385. R.E. is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC (Fox Chase Cancer Center) is supported by The University of Kansas Cancer Center (Grant No. P30-CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by Grants No. 5U01-CA113916 and R01-CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GCHBOC) was supported by the German Cancer Aid (Grant No. 110837; to R.K.S.). GEMO (Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers) was supported by the Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award; the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer. Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study: National Cancer Genetics Network UNICANCER Genetic Group, France. Ghent University Hospital (G-FAST): M.V.H. obtained funding from IWT. HCSC (Hospital Clinico San Carlos) was supported by Grants No. RD12/00369/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS (Helsinki Breast Cancer Study) was supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. The HEBON study is supported by the Dutch Cancer Society Grants No. NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research Grant No. NWO 91109024, the Pink Ribbon Grants No. 110005 and 2014-187.WO76, the BBMRI Grant No. NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants No. KTIA-OTKA CK-80745 and OTKA K-112228. HVH (University Hospital Vall d’Hebron) was supported by Spanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds: FIS PI12/02585 to O.D. and FIS PI13/01711 to S.G.-E. S.G.-E. is funded by Miguel Servet contract (ISCiii). ICO (Institut Catala d` ’Oncologia) contract grant sponsor: Asociacion Española Contra el C ´ ancer, Spanish Health Research Fund; ´ Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia; Contract Grants No.: ISCIIIRETIC RD06/ 0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT (INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility) was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade Grant No. PSR-SIIRI-701. IOVHBOCS (Istituto Oncologico Veneto Hereditary Breast and Ovarian Cancer Study) was supported by Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. IPOBCS (Portuguese Oncology Institute-Porto Breast Cancer Study) was supported by Liga Portuguesa Contra o Cancro. kConFab (Kathleen Cuningham Consortium for Research into Familial Breast Cancer) was supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The Clinical Follow Up Study received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the US NIH. A.B.S. is supported by an NHMRC senior research Fellowship (APP1061779). Curation of CIMBA variant nomenclature and classification in the Spurdle laboratory was supported by funding from the Cancer Council Queensland (APP1086286). KOHBRA (Korean Hereditary Breast Cancer Study) was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). KUMC (University of Kansas Medical Center) was supported by the University of Kansas Cancer Center (Grant No. P30- CA168524). MAYO (Mayo Clinic) was supported by NIH Grants No. CA116167, CA128978, and CA176785, a National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (Grant No. CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation. McGill University was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Memorial Sloan Kettering Cancer Center was supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NCI research of M.H.G. and J.T.L was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. OSUCCG (The Ohio State University Comprehensive Cancer Center) was supported by the Ohio State University Comprehensive Cancer Center. SEABASS (South East Asian Breast Cancer Association Study) was supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. The Malaysian Breast Cancer Genetic Study is funded by research grants from the Malaysian Ministry of Science, Technology, and Innovation, Ministry of Higher Education (UM.C/HIR/MOHE/06), and charitable funding from Cancer Research Initiatives Foundation. SWE-BRCA (Swedish Breast Cancer Study) collaborators are supported by the Swedish Cancer Society. University of Chicago was supported by National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), Grants No. R01-CA142996 and 1U01-CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance, and the Breast Cancer Research Foundation. University of Pennsylvania was supported by Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. University of Pittsburg MageeWomen’s Hospital was supported by Frieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG) was supported by Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation