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, EMBRACE, GEMO Study Collaborators, Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer (HEBON)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

128 Citations (Scopus)
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BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2mutations. 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.


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 BRCA1mutations 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.

Original languageEnglish
Pages (from-to)2240-2250
Number of pages11
JournalJournal of Clinical Oncology
Issue number20
Early online date27 Apr 2017
Publication statusPublished - 10 Jul 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 by American Society of Clinical Oncology.All rights reserved.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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