• 編者按：本文卡司陣容豪華，作者達(dá)181位，來(lái)自歐美亞洲各大知名學(xué)府和研究機(jī)構(gòu)，包括：英國(guó)劍橋大學(xué)、威康基金會(huì)桑格研究所、曼徹斯特大學(xué)、南安普敦大學(xué)、謝菲爾德兒童醫(yī)院、伯明翰大學(xué)女子醫(yī)院、牛津大學(xué)丘吉爾醫(yī)院、倫敦大學(xué)圣喬治學(xué)院、倫敦癌癥研究院、倫敦兒童醫(yī)院、皇家馬斯登醫(yī)院、蓋伊和圣托馬斯醫(yī)院、南格拉斯哥大學(xué)、意大利國(guó)家腫瘤研究院、意大利癌癥研究基金會(huì)、意大利國(guó)家癌癥研究院、羅馬大學(xué)、摩德納大學(xué)、烏迪內(nèi)大學(xué)、比薩大學(xué)、加拿大魁北克大學(xué)、拉瓦爾大學(xué)、多倫多大學(xué)、多倫多西奈山醫(yī)院、澳大利亞墨爾本大學(xué)、彼得麥卡倫癌癥中心、美國(guó)國(guó)家癌癥研究院、加利福尼亞癌癥預(yù)防研究院、希望之城、猶他大學(xué)、堪薩斯大學(xué)、哈佛大學(xué)陳曾熙公共衛(wèi)生學(xué)院、達(dá)納法伯癌癥研究院、紀(jì)念斯隆凱特林癌癥中心、俄亥俄州立大學(xué)、芝加哥大學(xué)、賓夕法尼亞大學(xué)、匹茲堡大學(xué)、梅奧醫(yī)院、立陶宛國(guó)家研究院創(chuàng)新醫(yī)學(xué)中心、丹麥哥本哈根大學(xué)、奧胡斯大學(xué)、奧爾堡大學(xué)、歐登塞大學(xué)、西班牙國(guó)家癌癥研究中心、西班牙罕見疾病網(wǎng)絡(luò)、馬德里大學(xué)、巴塞羅那大學(xué)、加泰羅尼亞腫瘤研究院、希臘國(guó)家科學(xué)研究中心、德國(guó)癌癥研究中心、海德堡大學(xué)、慕尼黑工業(yè)大學(xué)、慕尼黑大學(xué)、維爾茨堡大學(xué)、明斯特大學(xué)、萊比錫大學(xué)、杜塞爾多夫海因里希海涅大學(xué)、漢諾威醫(yī)科大學(xué)、科隆大學(xué)、德累斯頓工業(yè)大學(xué)、基爾大學(xué)、烏爾姆大學(xué)、法國(guó)里昂大學(xué)、巴黎居里研究院、比利時(shí)根特大學(xué)、芬蘭赫爾辛基大學(xué)、荷蘭萊頓大學(xué)、匈牙利布達(dá)佩斯國(guó)家腫瘤研究院、冰島大學(xué)、葡萄牙腫瘤研究院、波爾圖大學(xué)、韓國(guó)首爾大學(xué)、蔚山大學(xué)、順天鄉(xiāng)大學(xué)、大林圣母醫(yī)院、奧地利維也納醫(yī)科大學(xué)、馬來(lái)西亞梳邦再也醫(yī)療中心、瑞典卡羅林斯卡大學(xué)（該校有一個(gè)委員會(huì)專門負(fù)責(zé)頒發(fā)諾貝爾生理學(xué)或醫(yī)學(xué)獎(jiǎng)）。

　　2017年4月27日，美國(guó)臨床腫瘤學(xué)會(huì)《臨床腫瘤學(xué)雜志》在線發(fā)表英國(guó)、意大利、加拿大、澳大利亞、美國(guó)、立陶宛、丹麥、西班牙、希臘、德國(guó)、法國(guó)、比利時(shí)、芬蘭、荷蘭、匈牙利、冰島、葡萄牙、韓國(guó)、奧地利、馬來(lái)西亞、瑞典95個(gè)機(jī)構(gòu)181位學(xué)者的研究報(bào)告，使用多基因風(fēng)險(xiǎn)評(píng)分（PRS）預(yù)測(cè)了男性乳腺癌易感基因突變攜帶者的乳腺癌和前列腺癌風(fēng)險(xiǎn)。

　　常見的乳腺癌易感基因（BRCA1/2）遺傳變異可改變女性BRCA1/2突變攜帶者的癌癥風(fēng)險(xiǎn)，BRCA1/2突變也可增加男性乳腺癌和前列腺癌的風(fēng)險(xiǎn)，該研究首次調(diào)查了男性BRCA1/2突變攜帶者乳腺癌和前列腺癌風(fēng)險(xiǎn)于常見遺傳變異的相關(guān)性及其對(duì)癌癥風(fēng)險(xiǎn)預(yù)測(cè)的意義。

　　該研究從BRCA1/2修飾基因研究者聯(lián)盟入組1802例男性BRCA1/2突變攜帶者，采用定制的腫瘤基因陣列測(cè)序技術(shù)進(jìn)行基因分型，利用已公布的效應(yīng)估計(jì)值作為權(quán)重，通過構(gòu)建加權(quán)PRS，調(diào)查已知乳腺癌和前列腺癌易感變異對(duì)男性BRCA1/2突變攜帶者癌癥風(fēng)險(xiǎn)的綜合影響。

　　結(jié)果發(fā)現(xiàn)，在男性BRCA1/2突變攜帶者中：

• 參考88個(gè)女性乳腺癌易感變異的PRS與乳腺癌風(fēng)險(xiǎn)有非常顯著的相關(guān)性（PRS標(biāo)準(zhǔn)差比值比：1.36，95%置信區(qū)間：1.19～1.56，P=0.0000086）。

• 參考103個(gè)前列腺癌易感變異的PRS與前列腺癌風(fēng)險(xiǎn)有非常顯著的相關(guān)性（PRS標(biāo)準(zhǔn)差比值比：1.56，95%置信區(qū)間：1.35～1.81，P=0.0000000032）。

• PRS分布兩端可見癌癥絕對(duì)風(fēng)險(xiǎn)存在巨大差異，例如在PRS第5、95百分位，BRCA1、BRCA2突變攜帶者年齡為80歲時(shí)的前列腺癌風(fēng)險(xiǎn)分別為7%～26%、19%～61%。

　　因此，對(duì)于男性BRCA1/2突變攜帶者，PRS可提供癌癥風(fēng)險(xiǎn)分層信息，可使這些男性及其醫(yī)師能夠?qū)θ橄侔┖颓傲邢侔╋L(fēng)險(xiǎn)管理的類型和時(shí)機(jī)進(jìn)行明智決策。

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