Breast and Prostate Cancer Risks for MaleBRCA1andBRCA2Pathogenic Variant Carriers Using Polygenic Risk Scores
Authors: Barnes Daniel R , Silvestri Valentina , Leslie Goska , McGuffog Lesley , Dennis Joe , Yang Xin , Adlard Julian , Agnarsson Bjarni A , Ahmed Munaza , Aittomäki Kristiina , Andrulis Irene L , Arason Adalgeir , Arnold Norbert , Auber Bernd , Azzollini Jacopo , Balmaña Judith , Barkardottir Rosa B , Barrowdale Daniel , Barwell Julian , Belotti Muriel , Benitez Javier , Berthet Pascaline , Boonen Susanne E , Borg Åke , Bozsik Aniko , Brady Angela F , Brennan Paul , Brewer Carole , Brunet Joan , Bucalo Agostino , Buys Saundra S , Caldés Trinidad , Caligo Maria A , Campbell Ian , Cassingham Hayley , Christensen Lise Lotte , Cini Giulia , Claes Kathleen B M ,   GEMO Study Collaborators,   EMBRACE Collaborators, Cook Jackie , Coppa Anna , Cortesi Laura , Damante Giuseppe , Darder Esther , Davidson Rosemarie , de la Hoya Miguel , De Leeneer Kim , de Putter Robin , Del Valle Jesús , Diez Orland , Ding Yuan Chun , Domchek Susan M , Donaldson Alan , Eason Jacqueline , Eeles Ros , Engel Christoph , Evans D Gareth , Feliubadaló Lidia , Fostira Florentia , Frone Megan , Frost Debra , Gallagher David , Gehrig Andrea , Giraud Sophie , Glendon Gord , Godwin Andrew K , Goldgar David E , Greene Mark H , Gregory Helen , Gross Eva , Hahnen Eric , Hamann Ute , Hansen Thomas V O , Hanson Helen , Hentschel Julia , Horvath Judit ,   KConFab Investigators,   HEBON Investigators, Izatt Louise , Izquierdo Angel , James Paul A , Janavicius Ramunas , Jensen Uffe Birk , Johannsson Oskar Th , John Esther M , Kramer Gero , Kroeldrup Lone , Kruse Torben A , Lautrup Charlotte , Lazaro Conxi , Lesueur Fabienne , Lopez-Fernández Adria , Mai Phuong L , Manoukian Siranoush , Matrai Zoltan , Matricardi Laura , Maxwell Kara N , Mebirouk Noura , Meindl Alfons , Montagna Marco , Monteiro Alvaro N , Morrison Patrick J , Muranen Taru A , Murray Alex , Nathanson Katherine L , Neuhausen Susan L , Nevanlinna Heli , Nguyen-Dumont Tu , Niederacher Dieter , Olah Edith , Olopade Olufunmilayo I , Palli Domenico , Parsons Michael T , Pedersen Inge Sokilde , Peissel Bernard , Perez-Segura Pedro , Peterlongo Paolo , Petersen Annabeth H , Pinto Pedro , Porteous Mary E , Pottinger Caroline , Pujana Miquel Angel , Radice Paolo , Ramser Juliane , Rantala Johanna , Robson Mark , Rogers Mark T , Rønlund Karina , Rump Andreas , Sánchez de Abajo Ana María , Shah Payal D , Sharif Saba , Side Lucy E , Singer Christian F , Stadler Zsofia , Steele Linda , Stoppa-Lyonnet Dominique , Sutter Christian , Tan Yen Yen , Teixeira Manuel R , Teulé Alex , Thull Darcy L , Tischkowitz Marc , Toland Amanda E , Tommasi Stefania , Toss Angela , Trainer Alison H , Tripathi Vishakha , Valentini Virginia , van Asperen Christi J , Venturelli Marta , Viel Alessandra , Vijai Joseph , Walker Lisa , Wang-Gohrke Shan , Wappenschmidt Barbara , Whaite Anna , Zanna Ines , Offit Kenneth , Thomassen Mads , Couch Fergus J , Schmutzler Rita K , Simard Jacques , Easton Douglas F , Chenevix-Trench Georgia , Antoniou Antonis C , Ottini Laura ,   the Consortium of Investigators of Modifiers of BRCA1 and BRCA2
Published: July 2021

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.