Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Daniel R Barnes, Valentina Silvestri, Goska Leslie, Lesley McGuffog, Joe Dennis, Xin Yang, Julian Adlard, Bjarni A Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L Andrulis, Adalgeir Arason, Norbert Arnold, Bernd Auber, Jacopo Azzollini, Judith Balmaña, Rosa B Barkardottir, Daniel Barrowdale, Julian Barwell, Muriel BelottiJavier Benitez, Pascaline Berthet, Susanne E Boonen, Åke Borg, Aniko Bozsik, Angela Brady, Paul Brennan, Carole Brewer, Joan Brunet, Agostino Bucalo, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Ian Campbell, Hayley Cassingham, Lise Lotte Christensen, Giulia Cini, Kathleen B M Claes, GEMO Study Collaborators, EMBRACE Collaborators, Jackie Cook, Anna Coppa, Laura Cortesi, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de la Hoya, Thomas V O Hansen, Charlotte Lautrup, Inge Sokilde Pedersen, Annabeth H Petersen, Mads Thomassen

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BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

METHODS: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.

Original languageEnglish
Article numberdjab147
JournalJournal of the National Cancer Institute
Publication statusE-pub ahead of print - 28 Jul 2021

Bibliographical note

© The Author(s) 2021. Published by Oxford University Press.


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