Common Susceptibility Loci for Male Breast Cancer

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.

Figure 1.

Regional association plots for 6q25.1 (A), 10p12.31 (B), and 11q13.3 (C) male breast cancer risk loci. Each point represents an individual single nucleotide polymorphism (SNP) sorted on the x-axis by physical position based on National Center for Biotechnology Information build 37 of the human genome and plotted by −log₁₀P value on the y-axis. Recombination rates, estimated using HapMap data, are plotted in blue. For each region, the published female breast cancer predisposition SNP is plotted as a circle alongside the variant most strongly associated with male breast cancer, plotted as a diamond. In instances where there are multiple independent predisposition loci at the same genomic region, pairs of SNPs are grouped by color. Lighter colors represent the genome-wide association study P value and darker colors the joint P value for the top SNPs. All statistical tests were 2-sided.

Figure 2.

Distributions of the 313-single nucleotide polymorphism polygenic risk scores (PRSs) in 1380 male breast cancer cases, 1671 female breast cancer cases, and 2663 controls. PRSs were standardized to mean = 0, SD = 1 using 2663 controls from the 1958 British Birth Cohort. The mean PRS was 0.44 in males and 0.41 in females.