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Common Susceptibility Loci for Male Breast Cancer.

Accepted version
Peer-reviewed

Type

Article

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Authors

Maguire, Sarah 
Perraki, Eleni 
Tomczyk, Katarzyna 
Jones, Michael E 
Fletcher, Olivia 

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.

Description

Keywords

Breast Neoplasms, Male, Case-Control Studies, Confidence Intervals, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linear Models, Linkage Disequilibrium, Male, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Estrogen

Journal Title

J Natl Cancer Inst

Conference Name

Journal ISSN

0027-8874
1460-2105

Volume Title

113

Publisher

Oxford University Press (OUP)

Rights

All rights reserved
Sponsorship
Cancer Research Uk (None)
Cancer Research UK (16565)