Common susceptibility loci for male breast cancer.
AuthorMaguire, S; Perraki, E; Tomczyk, K; Jones, ME; Fletcher, O; Pugh, M; Winter, T; Thompson, K; Cooke, R; kConFab Consortium; ...
Source TitleJournal of the National Cancer Institute
PublisherOxford University Press (OUP)
AffiliationSir Peter MacCallum Department of Oncology
Medicine and Radiology
Document TypeJournal Article
CitationsMaguire, S., Perraki, E., Tomczyk, K., Jones, M. E., Fletcher, O., Pugh, M., Winter, T., Thompson, K., Cooke, R., kConFab Consortium, Trainer, A., James, P., Bojesen, S., Flyger, H., Nevanlinna, H., Mattson, J., Friedman, E., Laitman, Y., Palli, D. ,... Orr, N. (2020). Common susceptibility loci for male breast cancer.. J Natl Cancer Inst, https://doi.org/10.1093/jnci/djaa101.
Access StatusOpen Access
BACKGROUND: The aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided. RESULTS: The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.
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