Breast and Prostate Cancer Risks for Male<i>BRCA1</i>and<i>BRCA2</i>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, Aðalgeir Arason, Norbert Arnold, Bernd Auber, Jacopo Azzollini, Judith Balmañà, Rósa B. Barkardóttir, Daniel Barrowdale, Julian Barwell, Muriel Belotti, Javier Benı́tez, Pascaline Berthet, Susanne E. Boonen, Åke Borg, Anikó Bozsik, Angela F. 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 Claes, GEMO Study Collaborators, EMBRACE Collaborators, Jackie Cook, Anna Coppa, Laura Cortesi, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de la Hoya, Kim De Leeneer, Robin De Putter, Jesús Del Valle, Orland Dı́ez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Rosalind A. Eeles, Christoph Engel, D. Gareth Evans, Lídia Feliubadaló, Florentia Fostira, Megan N. Frone, Debra Frost, David Gallagher, Andrea Gehrig, Sophie Giraud, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Helen Gregory, Eva Groß, Eric Hahnen, Ute Hamann, Thomas van Overeem Hansen, Helen Hanson, Julia Hentschel, Judit Horváth, KConFab Investigators, HEBON Investigators, Louise Izatt, Á. Izquierdo, Paul A. James, Ramūnas Janavičius, Uffe Birk Jensen, Oskar T. Johannsson, Esther M. John, Gero Kramer, Lone Kroeldrup, Torben A. Kruse, Charlotte Kvist Lautrup, Conxi Lázaro, Fabienne Lesueur, Adrià López‐Fernández, Phuong L Mai, Siranoush Manoukian, Zoltán Mátrai, Laura Matricardi, Kara N. Maxwell, Noura Mebirouk, Alfons Meindl
Abstract
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 1318 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 3 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 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios 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 informing clinical management.