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

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

Research output: Contribution to journalArticle

52 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)2240-2250
Number of pages11
JournalJournal of Clinical Oncology
Volume35
Issue number20
DOIs
StatePublished - Jul 10 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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