The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK.
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
J Natl Cancer Inst. 2021 Apr 6;113(4):453-461. doi: 10.1093/jnci/djaa101.
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.
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.
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).
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.
男性乳腺癌（MBC）的病因尚不清楚。特别是，MBC 的遗传基础与女性乳腺癌（FBC）的差异程度尚不清楚。先前对 MBC 的全基因组关联研究确定了该疾病的 2 个易感性基因座，这两个基因座也与 FBC 的风险相关。
我们在 3 个阶段对欧洲裔 MBC 病例对照进行了全基因组单核苷酸多态性基因分型。使用 1380 例病例和 3620 例对照的固定效应荟萃分析评估了直接基因分型和推断的单核苷酸多态性与 MBC 之间的关联。对 810 例病例和 1026 例对照进行了复制基因分型，以验证 P 值小于 1×10-06 的变体。使用连锁不平衡评分回归评估与 FBC 的遗传相关性，通过综合检查已发表的 FBC 风险基因座与 MBC 风险的关联，以及评估 FBC 多基因风险评分与 MBC 之间的关联来评估。所有统计检验均为双侧。
全基因组关联研究确定了 3 个新的 MBC 易感性基因座，这些基因座达到了全基因组统计学意义（P < 5×10-08）。遗传相关性分析显示，与雌激素受体阳性 FBC 具有很强的共同遗传基础。遗传风险最高五分位的男性患乳腺癌的风险是遗传风险最低五分位的男性的四倍（比值比=3.86，95%置信区间=3.07 至 4.87，P=2.08×10-30）。
这些发现增进了我们对 MBC 遗传基础的理解，为 FBC 和 MBC 之间具有重叠遗传病因学提供了支持，并确定了一个四倍高风险的易感男性群体。
