Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.
Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.
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DOI：
10.1200/jco.2016.69.4935
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发表时间：
2017-07-10
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影响因子：
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通讯作者：
Ottini L
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作者：
Lecarpentier J;Silvestri V;Kuchenbaecker KB;Barrowdale D;Dennis J;McGuffog L;Soucy P;Leslie G;Rizzolo P;Navazio AS;Valentini V;Zelli V;Lee A;Amin Al Olama A;Tyrer JP;Southey M;John EM;Conner TA;Goldgar DE;Buys SS;Janavicius R;Steele L;Ding YC;Neuhausen SL;Hansen TVO;Osorio A;Weitzel JN;Toss A;Medici V;Cortesi L;Zanna I;Palli D;Radice P;Manoukian S;Peissel B;Azzollini J;Viel A;Cini G;Damante G;Tommasi S;Peterlongo P;Fostira F;Hamann U;Evans DG;Henderson A;Brewer C;Eccles D;Cook J;Ong KR;Walker L;Side LE;Porteous ME;Davidson R;Hodgson S;Frost D;Adlard J;Izatt L;Eeles R;Ellis S;Tischkowitz M;EMBRACE;Godwin AK;Meindl A;Gehrig A;Dworniczak B;Sutter C;Engel C;Niederacher D;Steinemann D;Hahnen E;Hauke J;Rhiem K;Kast K;Arnold N;Ditsch N;Wang-Gohrke S;Wappenschmidt B;Wand D;Lasset C;Stoppa-Lyonnet D;Belotti M;Damiola F;Barjhoux L;Mazoyer S;GEMO Study Collaborators;Van Heetvelde M;Poppe B;De Leeneer K;Claes KBM;de la Hoya M;Garcia-Barberan V;Caldes T;Perez Segura P;Kiiski JI;Aittomäki K;Khan S;Nevanlinna H;van Asperen CJ;HEBON;Vaszko T;Kasler M;Olah E;Balmaña J;Gutiérrez-Enríquez S;Diez O;Teulé A;Izquierdo A;Darder E;Brunet J;Del Valle J;Feliubadalo L;Pujana MA;Lazaro C;Arason A;Agnarsson BA;Johannsson OT;Barkardottir RB;Alducci E;Tognazzo S;Montagna M;Teixeira MR;Pinto P;Spurdle AB;Holland H;KConFab Investigators;Lee JW;Lee MH;Lee J;Kim SW;Kang E;Kim Z;Sharma P;Rebbeck TR;Vijai J;Robson M;Lincoln A;Musinsky J;Gaddam P;Tan YY;Berger A;Singer CF;Loud JT;Greene MH;Mulligan AM;Glendon G;Andrulis IL;Toland AE;Senter L;Bojesen A;Nielsen HR;Skytte AB;Sunde L;Jensen UB;Pedersen IS;Krogh L;Kruse TA;Caligo MA;Yoon SY;Teo SH;von Wachenfeldt A;Huo D;Nielsen SM;Olopade OI;Nathanson KL;Domchek SM;Lorenchick C;Jankowitz RC;Campbell I;James P;Mitchell G;Orr N;Park SK;Thomassen M;Offit K;Couch FJ;Simard J;Easton DF;Chenevix-Trench G;Schmutzler RK;Antoniou AC;Ottini L
BRCA 1/2突变会增加男性患乳腺癌和前列腺癌的风险。常见的遗传变异改变了BRCA 1/2突变女性携带者的癌症风险。我们首次调查了BRCA 1/2突变男性携带者常见遗传变异与乳腺癌和前列腺癌风险的关系，以及对癌症风险预测的影响。我们使用定制的Illumina OncoArray对来自BRCA 1/2修饰物研究者联盟的1，802名BRCA 1/2突变男性携带者进行基因分型。我们研究了乳腺癌和前列腺癌易感性变异对BRCA 1/2突变男性携带者癌症风险的综合影响，方法是使用已发表的效应估计值作为权重构建加权多基因风险评分（PRS）。在BRCA 1/2突变的男性携带者中，基于88种女性乳腺癌易感性变异的PRS与乳腺癌风险相关（PRS标准差的比值比，1.36; 95%CI，1.19 - 1.56; P = 8.6 × 10−6）。类似地，基于103种前列腺癌易感性变异的PRS与前列腺癌风险相关（PRS标准差的比值比为1.56; 95%CI为1.35 - 1.81; P = 3.2 × 10−9）。在PRS分布的极端情况下，观察到绝对癌症风险的巨大差异。例如，在PRS的第5次和第95次筛查时，80岁以下的BRCA 1突变携带者和BRCA 2突变携带者的前列腺癌风险分别为7%至26%和19%至61%。PRS可以为BRCA 1/2突变的男性携带者提供信息性的癌症风险分层，这可能使这些男性及其医生能够就乳腺癌和前列腺癌风险管理的类型和时间做出明智的决定。
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. 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. 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. 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.