Common Susceptibility Loci for Male Breast Cancer. (12th August 2020)

• Record Type: Journal Article
• Authors: Maguire, Sarah; Perraki, Eleni; Tomczyk, Katarzyna; Jones, Michael E; Fletcher, Olivia; Pugh, Matthew; Winter, Timothy; Thompson, Kyle; Cooke, Rosie; Trainer, Alison; James, Paul; Bojesen, Stig; Flyger, Henrik; Nevanlinna, Heli; Mattson, Johanna; Friedman, Eitan; Laitman, Yael; Palli, Domenico; Masala, Giovanna; Zanna, Ines; Ottini, Laura; Silvestri, Valentina; Hollestelle, Antoinette; Hooning, Maartje J; Novaković, Srdjan; Krajc, Mateja; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Olsson, Hakan; Hedenfalk, Ingrid; Saloustros, Emmanouil; Georgoulias, Vasilios; Easton, Douglas F; Pharoah, Paul; Dunning, Alison M; Bishop, D Timothy; Neuhausen, Susan L; Steele, Linda; Ashworth, Alan; Garcia Closas, Montserrat; Houlston, Richard; Swerdlow, Anthony; Orr, Nick;
• Is Part Of: Journal of the National Cancer Institute. Volume 113:Number 4(2021)
• Page Start: 453
• Page End: 461
• Publication Date: 2020-08-12
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djaa101
• Languages: English
• ISSNs: 0027-8874

Abstract

Abstract: Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10 –06 . Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance ( P < 5 × 10 –08 ). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor–positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10 –30 ). Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.