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Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores

Lookup NU author(s): Alexander Henderson, Ian Campbell

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Abstract

© 2017 by American Society of Clinical Oncology.All rights reserved. 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 Wegenotyped 1,802male carriers ofBRCA1/2mutations fromthe Consortiumof Investigators ofModifiers 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 formale 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 variantswas associatedwith breast cancer risk (odds ratio per standard deviation of PRS, 1.36;95%CI, 1.19 to 1.56; P = 8.6 3 1026). 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=3.23 1029). 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.

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Author(s): Lecarpentier J, Kuchenbaecker KB, Barrowdale D, Dennis J, McGuffog L, Leslie G, Lee A, Al Olama AA, Tyrer JP, Frost D, Ellis S, Easton DF, Antoniou AC, Tischkowitz M, Evans DG, Henderson A, Brewer C, Eccles D, Cook J, Ong K-R, Walker L, Side LE, Hodgson S, Izatt L, Eeles R, Orr N, Porteous ME, Davidson R, Adlard J, Silvestri V, Rizzolo P, Navazio AS, Valentini V, Zelli V, Ottini L, Toss A, Medici V, Cortesi L, Zanna I, Palli D, Radice P, Manoukian S, Peissel B, Azzollini J, Peterlongo P, Viel A, Cini G, Damante G, Tommasi S, Alducci E, Tognazzo S, Montagna M, Caligo MA, Soucy P, Simard J, Mulligan AM, Andrulis IL, Glendon G, Southey M, Campbell I, James P, Mitchell G, Spurdle AB, Holland H, Chenevix-Trench G, John EM, Steele L, Ding YC, Neuhausen SL, Weitzel JN, Conner TA, Buys SS, Goldgar DE, Godwin AK, Sharma P, Rebbeck TR, Vijai J, Robson M, Lincoln A, Musinsky J, Gaddam P, Offit K, Loud JT, Greene MH, Toland AE, Senter L, Huo D, Nielsen SM, Olopade OI, Nathanson KL, Domchek SM, Lorenchick C, Jankowitz RC, Couch FJ, Janavicius R, Hansen TVO, Bojesen A, Nielsen HR, Skytte A-B, Sunde L, Jensen UB, Pedersen IS, Krogh L, Kruse TA, Thomassen M, Osorio A, De La Hoya M, Garcia-Barberan V, Caldes T, Segura PP, Balmana J, Gutierrez-Enriquez S, Diez O, Teule A, Del Valle J, Feliubadalo L, Pujana MA, Lazaro C, Izquierdo A, Darder E, Brunet J, Fostira F, Hamann U, Sutter C, Meindl A, Ditsch N, Gehrig A, Dworniczak B, Engel C, Wand D, Niederacher D, Steinemann D, Hahnen E, Hauke J, Rhiem K, Wappenschmidt B, Schmutzler RK, Kast K, Arnold N, Wang-Gohrke S, Lasset C, Damiola F, Barjhoux L, Mazoyer S, Stoppa-Lyonnet D, Belotti M, Van Heetvelde M, Poppe B, De Leeneer K, Claes KBM, Kiiski JI, Khan S, Nevanlinna H, Aittomaki K, Vvan Asperen CJ, Vaszko T, Kasler M, Olah E, Arason A, Agnarsson BA, Johannsson OTh, Barkardottir RB, Teixeira MR, Pinto P, Lee JW, Lee MH, Lee J, Kim S-W, Kang E, Park SK, Kim Z, Tan YY, Berger A, Singer CF, Yoon S-Y, Teo S-H, Von Wachenfeldt A

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Oncology

Year: 2017

Volume: 35

Issue: 20

Pages: 2240-2250

Print publication date: 10/07/2017

Online publication date: 27/04/2017

Acceptance date: 02/04/2016

Date deposited: 07/08/2017

ISSN (print): 0732-183X

ISSN (electronic): 1527-7755

Publisher: American Society of Clinical Oncology

URL: https://doi.org/10.1200/JCO.2016.69.4935

DOI: 10.1200/JCO.2016.69.4935

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