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

Lecarpentier J 1 , Silvestri V 1 , Kuchenbaecker KB 1 , Barrowdale D 1 , Dennis J 1 , McGuffog L 1 Show all authors , Soucy P 1 , Leslie G 1 , Rizzolo P 1 , Navazio AS 1 , Valentini V 1 , Zelli V 1 , Lee A 1 , Amin Al Olama A 1 , Tyrer JP 1 , Southey M 1 , John EM 1 , Conner TA 1 , Goldgar DE 1 , Buys SS 1 , Janavicius R 1 , Steele L 1 , Ding YC 1 , Neuhausen SL 1 , Hansen TVO 1 , Osorio A 1 , Weitzel JN 1 , Toss A 1 , Medici V 1 , Cortesi L 1 , Zanna I 1 , Palli D 1 , Radice P 1 , Manoukian S 1 , Peissel B 1 , Azzollini J 1 , Viel A 1 , Cini G 1 , Damante G 1 , Tommasi S 1 , Peterlongo P 1 , Fostira F 1 , Hamann U 1 , Evans DG 1 , Henderson A 1 , Brewer C 1 , Eccles D 1 , Cook J 1 , Ong KR 1 , Walker L 1 , Side LE 1 , Porteous ME 1 , Davidson R 1 , Hodgson S 1 , Frost D 1 , Adlard J 1 , Izatt L 1 , Eeles R 1 , Ellis S 1 , Tischkowitz M 1 , EMBRACE , Godwin AK 1 , Meindl A 1 , Gehrig A 1 , Dworniczak B 1 , Sutter C 1 , Engel C 1 , Niederacher D 1 , Steinemann D 1 , Hahnen E 1 , Hauke J 1 , Rhiem K 1 , Kast K 1 , Arnold N 1 , Ditsch N 1 , Wang-Gohrke S 1 , Wappenschmidt B 1 , Wand D 1 , Lasset C 1 , Stoppa-Lyonnet D 1 , Belotti M 1 , Damiola F 1 , Barjhoux L 1 , Mazoyer S 1 , GEMO Study Collaborators , Van Heetvelde M 1 , Poppe B 1 , De Leeneer K 1 , Claes KBM 1 , de la Hoya M 1 , Garcia-Barberan V 1 , Caldes T 1 , Perez Segura P 1 , Kiiski JI 1 , Aittomäki K 1 , Khan S 1 , Nevanlinna H 1 , van Asperen CJ 1 , HEBON , Vaszko T 1 , Kasler M 1 , Olah E 1 , Balmaña J 1 , Gutiérrez-Enríquez S 1 , Diez O 1 , Teulé A 1 , Izquierdo A 1 , Darder E 1 , Brunet J 1 , Del Valle J 1 , Feliubadalo L 1 , Pujana MA 1 , Lazaro C 1 , Arason A 1 , Agnarsson BA 1 , Johannsson OT 1 , Barkardottir RB 1 , Alducci E 1 , Tognazzo S 1 , Montagna M 1 , Teixeira MR 1 , Pinto P 1 , Spurdle AB 1 , Holland H 1 , KConFab Investigators , Lee JW 1 , Lee MH 1 , Lee J 1 , Kim SW 1 , Kang E 1 , Kim Z 1 , Sharma P 1 , Rebbeck TR 1 , Vijai J 1 , Robson M 1 , Lincoln A 1 , Musinsky J 1 , Gaddam P 1 , Tan YY 1 , Berger A 1 , Singer CF 1 , Loud JT 1 , Greene MH 1 , Mulligan AM 1 , Glendon G 1 , Andrulis IL 1 , Toland AE 1 , Senter L 1 , Bojesen A 1 , Nielsen HR 1 , Skytte AB 1 , Sunde L 1 , Jensen UB 1 , Pedersen IS 1 , Krogh L 1 , Kruse TA 1 , Caligo MA 1 , Yoon SY 1 , Teo SH 1 , von Wachenfeldt A 1 , Huo D 1 , Nielsen SM 1 , Olopade OI 1 , Nathanson KL 1 , Domchek SM 1 , Lorenchick C 1 , Jankowitz RC 1 , Campbell I 1 , James P 1 , Mitchell G 1 , Orr N 1 , Park SK 1 , Thomassen M 1 , Offit K 1 , Couch FJ 1 , Simard J 1 , Easton DF 1 , Chenevix-Trench G 1 , Schmutzler RK 1 , Antoniou AC 1 , Ottini L 1

Affiliations 

  • 1 Julie Lecarpentier, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Goska Leslie, Andrew Lee, Ali Amin Al Olama, Jonathan P. Tyrer, Debra Frost, Steve Ellis, Douglas F. Easton, and Antonis C. Antoniou, University of Cambridge; Karoline B. Kuchenbaecker, The Wellcome Trust Sanger Institute, Hinxton; Marc Tischkowitz, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge; D. Gareth Evans, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester; Alex Henderson, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Carole Brewer, Royal Devon and Exeter Hospital, Exeter; Diana Eccles, Southampton University Hospitals NHS Trust, Southampton; Jackie Cook, Sheffield Children's Hospital, Sheffield; Kai-ren Ong, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham; Lisa Walker, Churchill Hospital, Oxford; Lucy E. Side, Great Ormond Street Hospital for Children NHS Trust; Shirley Hodgson, St George's, University of London; Louise Izatt, Guy's and St Thomas' NHS Foundation Trust; Ros Eeles, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Nick Orr, The Institute of Cancer Research, London; Mary E. Porteous, Western General Hospital, Edinburgh; Rosemarie Davidson, South Glasgow University Hospitals, Glasgow; Julian Adlard, Chapel Allerton Hospital, Leeds, United Kingdom; Valentina Silvestri, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, and Laura Ottini, Sapienza University of Rome, Rome; Angela Toss, Veronica Medici, and Laura Cortesi, University of Modena and Reggio Emilia, Modena; Ines Zanna and Domenico Palli, Cancer Research and Prevention Institute, Florence; Paolo Radice, Siranoush Manoukian, Bernard Peissel, and Jacopo Azzollini, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (INT); Paolo Peterlongo, Italian Foundation for Cancer Research Institute of Molecular Oncology (IFOM), Milan; Alessandra Viel and Giulia Cini, CRO Aviano, National Cancer Institute, Aviano; Giuseppe Damante, University of Udine, Udine; Stefania Tommasi, Istituto Nazionale Tumori "Giovanni Paolo II", Bari; Elisa Alducci, Silvia Tognazzo, and Marco Montagna, Veneto Institute of Oncology IOV - IRCCS, Padua; Maria A. Caligo, University and University Hospital of Pisa, Pisa, Italy; Penny Soucy and Jacques Simard, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec; Anna Marie Mulligan and Irene L. Andrulis, University of Toronto; Gord Glendon and Irene L. Andrulis, Mount Sinai Hospital, Toronto, Ontario, Canada; Melissa Southey, Ian Campbell, Paul James, and Gillian Mitchell, University of Melbourne, Parkville, Victoria; Amanda B. Spurdle, Helene Holland, and Georgia Chenevix-Trench, QIMR Berghofer Medical Research Institute, Brisbane, Queensland; Ian Campbell, Paul James, and Gillian Mitchell, Peter MacCallum Cancer Centre, East Melbourne, New South Wales, Australia; Esther M. John, Cancer Prevention Institute of California, Fremont; Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, and Jeffrey N. Weitzel, City of Hope, Duarte, CA; Thomas A. Conner and Saundra S. Buys, Huntsman Cancer Institute; David E. Goldgar, University of Utah School of Medicine, Salt Lake City, UT; Andrew K. Godwin, University of Kansas Medical Center, Kansas City; Priyanka Sharma, University of Kansas Medical Center, Westwood, KS; Timothy R. Rebbeck, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, MA; Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, and Kenneth Offit, Memorial Sloan Kettering Cancer Center, New York, NY; Jennifer T. Loud and Mark H. Greene, National Cancer Institute, Bethesda, MD; Amanda Ewart Toland and Leigha Senter, The Ohio State University, Columbus, OH; Dezheng Huo, Sarah M. Nielsen, and Olufunmilayo I. Olopade, University of Chicago Medical Center, Chicago, IL; Katherine L. Nathanson and Susan M. Domchek, University of Pennsylvania, Philadelphia; Christa Lorenchick and Rachel C. Jankowitz, University of Pittsburgh Medical Center, Pittsburgh, PA; Fergus J. Couch, Mayo Clinic, Rochester, MN; Ramunas Janavicius, State Research Institute Innovative Medicine Center, Vilnius, Lithuania; Thomas V.O. Hansen, Rigshospitalet, Copenhagen University Hospital, Copenhagen; Anders Bojesen and Henriette Roed Nielsen, Vejle Hospital, Vejle; Anne-Bine Skytte, Lone Sunde, and Uffe Birk Jensen, Aarhus University Hospital, Aarhus; Inge Sokilde Pedersen, Aalborg University Hospital, Aalborg; Lotte Krogh, Torben A. Kruse, and Mads Thomassen, Odense University Hospital, Odense, Denmark; Ana Osorio, National Cancer Research Centre and Spanish Network on Rare Diseases; Miguel de la Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, and Pedro Perez Segura, Hospital Clinico San Carlos, El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid; Judith Balmaña, University Hospital, Vall d'Hebron; Sara Gutiérrez-Enríquez and Orland Diez, Vall d'Hebron Institute of Oncology; Orland Diez, University Hospital Vall d'Hebron; Alex Teulé, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, and Conxi Lazaro, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona; Angel Izquierdo, Esther Darder, and Joan Brunet, Institut d'Investigació Biomèdica de Girona, Catalan Institute of Oncology, Girona, Spain; Florentia Fostira, National Centre for Scientific Research "Demokritos," Athens, Greece; Ute Hamann, German Cancer Research Center (DKFZ); Christian Sutter, University Hospital Heidelberg, Heidelberg; Alfons Meindl, Klinikumrechts der Isar, Technical University Munich; Nina Ditsch, Ludwig-Maximilian University, Munich; Andrea Gehrig, University Würzburg, Würzburg; Bernd Dworniczak, University of Münster, Münster; Christoph Engel, University of Leipzig; Dorothea Wand, University Hospital, Leipzig; Dieter Niederacher, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf; Doris Steinemann, Hannover Medical School, Hannover; Eric Hahnen, Jan Hauke, Kerstin Rhiem, Barbara Wappenschmidt, and Rita K. Schmutzler, University Hospital Cologne, Cologne; Karin Kast, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden; Norbert Arnold, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Kiel; Shan Wang-Gohrke, University Hospital Ulm, Ulm, Germany; Christine Lasset, Francesca Damiola, and Laure Barjhoux, Centre Léon Bérard; Sylvie Mazoyer, University of Lyon, Lyon; Dominique Stoppa-Lyonnet and Muriel Belotti, Institut Curie, Paris, France; Mattias Van Heetvelde, Bruce Poppe, Kim De Leeneer, and Kathleen B.M. Claes, Ghent University, Gent, Belgium; Johanna I. Kiiski, Sofia Khan, and Heli Nevanlinna, University of Helsinki; Johanna I. Kiiski, Kristiina Aittomäki, Sofia Khan, and Heli Nevanlinna, Helsinki University Hospital, Helsinki, Finland; Christi J. van Asperen, Leiden University Medical Center, Leiden, the Netherlands; Tibor Vaszko, Miklos Kasler, and Edith Olah, National Institute of Oncology, Budapest, Hungary; Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th. Johannsson, and Rosa B. Barkardottir, Landspitali University Hospital and Biomedical Centre, University of Iceland, Reykjavik, Iceland; Manuel R. Teixeira and Pedro Pinto, Portuguese Oncology Institute; Manuel R. Teixeira, Porto University, Porto, Portugal; Jong Won Lee, Ulsan College of Medicine and Asan Medical Center; Min Hyuk Lee and Jihyoun Lee, Soonchunhyang University and Hospital; Sung-Won Kim and Eunyoung Kang, Daerim St Mary's Hospital; Sue Kyung Park, Seoul National University College of Medicine, Seoul; Zisun Kim, Soonchunhyang University Bucheon Hospital, Bucheon, Korea; Yen Y. Tan, Andreas Berger, and Christian F. Singer, Medical University of Vienna, Vienna, Austria; Sook-Yee Yoon and Soo-Hwang Teo, Sime Darby Medical Centre, Subang Jaya, Malaysia; and Anna von Wachenfeldt, Karolinska University Hospital, Stockholm, Sweden
J Clin Oncol, 2017 Jul 10;35(20):2240-2250.
PMID: 28448241 DOI: 10.1200/JCO.2016.69.4935

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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