Abstract
Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.
Highlights
Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer
We identify 244 germline pathogenic variants and we show demographic and clinical characteristics of patients with pathogenic variants
When we examined the age at diagnosis of breast cancer by gene, we found that the patients with pathogenic variants in PTEN, BRCA1, and BRCA2 were significantly younger at diagnosis compared to patients without pathogenic variants (Table 3)
Summary
Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. We identified 75 pathogenic variants (Supplementary Data 2) in 13 of 53 (24.5%) male breast cancer patients and 129 of 12,490 (1.0%) male controls (Fisher’s exact test, P = 1.64 × 10−14, OR = 31.1, Supplementary Table 5).
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