男性乳腺癌易感基因突变携带者的乳腺癌和前列腺癌风险预测

• 编者按：本文卡司阵容豪华，作者达181位，来自欧美亚洲各大知名学府和研究机构，包括：英国剑桥大学、威康基金会桑格研究所、曼彻斯特大学、南安普敦大学、谢菲尔德儿童医院、伯明翰大学女子医院、牛津大学丘吉尔医院、伦敦大学圣乔治学院、伦敦癌症研究院、伦敦儿童医院、皇家马斯登医院、盖伊和圣托马斯医院、南格拉斯哥大学、意大利国家肿瘤研究院、意大利癌症研究基金会、意大利国家癌症研究院、罗马大学、摩德纳大学、乌迪内大学、比萨大学、加拿大魁北克大学、拉瓦尔大学、多伦多大学、多伦多西奈山医院、澳大利亚墨尔本大学、彼得麦卡伦癌症中心、美国国家癌症研究院、加利福尼亚癌症预防研究院、希望之城、犹他大学、堪萨斯大学、哈佛大学陈曾熙公共卫生学院、达纳法伯癌症研究院、纪念斯隆凯特林癌症中心、俄亥俄州立大学、芝加哥大学、宾夕法尼亚大学、匹兹堡大学、梅奥医院、立陶宛国家研究院创新医学中心、丹麦哥本哈根大学、奥胡斯大学、奥尔堡大学、欧登塞大学、西班牙国家癌症研究中心、西班牙罕见疾病网络、马德里大学、巴塞罗那大学、加泰罗尼亚肿瘤研究院、希腊国家科学研究中心、德国癌症研究中心、海德堡大学、慕尼黑工业大学、慕尼黑大学、维尔茨堡大学、明斯特大学、莱比锡大学、杜塞尔多夫海因里希海涅大学、汉诺威医科大学、科隆大学、德累斯顿工业大学、基尔大学、乌尔姆大学、法国里昂大学、巴黎居里研究院、比利时根特大学、芬兰赫尔辛基大学、荷兰莱顿大学、匈牙利布达佩斯国家肿瘤研究院、冰岛大学、葡萄牙肿瘤研究院、波尔图大学、韩国首尔大学、蔚山大学、顺天乡大学、大林圣母医院、奥地利维也纳医科大学、马来西亚梳邦再也医疗中心、瑞典卡罗林斯卡大学（该校有一个委员会专门负责颁发诺贝尔生理学或医学奖）。

　　2017年4月27日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表英国、意大利、加拿大、澳大利亚、美国、立陶宛、丹麦、西班牙、希腊、德国、法国、比利时、芬兰、荷兰、匈牙利、冰岛、葡萄牙、韩国、奥地利、马来西亚、瑞典95个机构181位学者的研究报告，使用多基因风险评分（PRS）预测了男性乳腺癌易感基因突变携带者的乳腺癌和前列腺癌风险。

　　常见的乳腺癌易感基因（BRCA1/2）遗传变异可改变女性BRCA1/2突变携带者的癌症风险，BRCA1/2突变也可增加男性乳腺癌和前列腺癌的风险，该研究首次调查了男性BRCA1/2突变携带者乳腺癌和前列腺癌风险于常见遗传变异的相关性及其对癌症风险预测的意义。

　　该研究从BRCA1/2修饰基因研究者联盟入组1802例男性BRCA1/2突变携带者，采用定制的肿瘤基因阵列测序技术进行基因分型，利用已公布的效应估计值作为权重，通过构建加权PRS，调查已知乳腺癌和前列腺癌易感变异对男性BRCA1/2突变携带者癌症风险的综合影响。

　　结果发现，在男性BRCA1/2突变携带者中：

• 参考88个女性乳腺癌易感变异的PRS与乳腺癌风险有非常显著的相关性（PRS标准差比值比：1.36，95%置信区间：1.19～1.56，P=0.0000086）。

• 参考103个前列腺癌易感变异的PRS与前列腺癌风险有非常显著的相关性（PRS标准差比值比：1.56，95%置信区间：1.35～1.81，P=0.0000000032）。

• PRS分布两端可见癌症绝对风险存在巨大差异，例如在PRS第5、95百分位，BRCA1、BRCA2突变携带者年龄为80岁时的前列腺癌风险分别为7%～26%、19%～61%。

　　因此，对于男性BRCA1/2突变携带者，PRS可提供癌症风险分层信息，可使这些男性及其医师能够对乳腺癌和前列腺癌风险管理的类型和时机进行明智决策。

J Clin Oncol. 2017 Apr 27. [Epub ahead of print]

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

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

University of Cambridge; The Wellcome Trust Sanger Institute, Hinxton; Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge; Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester; Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Royal Devon and Exeter Hospital, Exeter; Southampton University Hospitals NHS Trust, Southampton; Sheffield Children's Hospital, Sheffield; Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham; Churchill Hospital, Oxford; Great Ormond Street Hospital for Children NHS Trust; St George's, University of London; Guy's and St Thomas' NHS Foundation Trust; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; The Institute of Cancer Research, London; Western General Hospital, Edinburgh; South Glasgow University Hospitals, Glasgow; Chapel Allerton Hospital, Leeds, United Kingdom; Sapienza University of Rome, Rome; University of Modena and Reggio Emilia, Modena; Cancer Research and Prevention Institute, Florence; Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (INT); Italian Foundation for Cancer Research Institute of Molecular Oncology (IFOM), Milan; CRO Aviano, National Cancer Institute, Aviano; University of Udine, Udine; Istituto Nazionale Tumori Giovanni Paolo II, Bari; Veneto Institute of Oncology IOV - IRCCS, Padua; University and University Hospital of Pisa, Pisa, Italy; Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec; University of Toronto; Mount Sinai Hospital, Toronto, Ontario, Canada; University of Melbourne, Parkville, Victoria; QIMR Berghofer Medical Research Institute, Brisbane, Queensland; Peter MacCallum Cancer Centre, East Melbourne, New South Wales, Australia; Cancer Prevention Institute of California, Fremont; City of Hope, Duarte, CA; Huntsman Cancer Institute; University of Utah School of Medicine, Salt Lake City, UT; University of Kansas Medical Center, Kansas City; University of Kansas Medical Center, Westwood, KS; Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, New York, NY; National Cancer Institute, Bethesda, MD; The Ohio State University, Columbus, OH; University of Chicago Medical Center, Chicago, IL; University of Pennsylvania, Philadelphia; University of Pittsburgh Medical Center, Pittsburgh, PA; Mayo Clinic, Rochester, MN; State Research Institute Innovative Medicine Center, Vilnius, Lithuania; Rigshospitalet, Copenhagen University Hospital, Copenhagen; Vejle Hospital, Vejle; Aarhus University Hospital, Aarhus; Aalborg University Hospital, Aalborg; Odense University Hospital, Odense, Denmark; National Cancer Research Centre and Spanish Network on Rare Diseases; Hospital Clinico San Carlos, El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid; University Hospital, Vall d'Hebron; Vall d'Hebron Institute of Oncology; University Hospital Vall d'Hebron; Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona; Institut d'Investigació Biomèdica de Girona, Catalan Institute of Oncology, Girona, Spain; National Centre for Scientific Research Demokritos, Athens, Greece; German Cancer Research Center (DKFZ); University Hospital Heidelberg, Heidelberg; Klinikumrechts der Isar, Technical University Munich; Ludwig-Maximilian University, Munich; University Würzburg, Würzburg; University of Münster, Münster; University of Leipzig; University Hospital, Leipzig; University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf; Hannover Medical School, Hannover; University Hospital Cologne, Cologne; University Hospital Carl Gustav Carus, Technical University Dresden, Dresden; University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Kiel; University Hospital Ulm, Ulm, Germany; Centre Léon Bérard; University of Lyon, Lyon; Institut Curie, Paris, France; Ghent University, Gent, Belgium; University of Helsinki; Helsinki University Hospital, Helsinki, Finland; Leiden University Medical Center, Leiden, the Netherlands; National Institute of Oncology, Budapest, Hungary; Landspitali University Hospital and Biomedical Centre, University of Iceland, Reykjavik, Iceland; Portuguese Oncology Institute; Porto University, Porto, Portugal; Ulsan College of Medicine and Asan Medical Center; Soonchunhyang University and Hospital; Daerim St Mary's Hospital; Seoul National University College of Medicine, Seoul; Soonchunhyang University Bucheon Hospital, Bucheon, Korea; Medical University of Vienna, Vienna, Austria; Sime Darby Medical Centre, Subang Jaya, Malaysia; Karolinska University Hospital, Stockholm, Sweden.

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.

DOI: 10.1200/JCO.2016.69.4935