Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls

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.

Fig. 1

Location and the number of frequent pathogenic variants in six genes in Japanese breast cancer women. Locations of frequent pathogenic variants found in patients and domains in proteins are shown by lollipop structures, with the variant type indicated by color. Pink, yellow, and green circles indicates loss of function, non-synonymous, and synonymous variants, respectively. The x-axis reflects the number of amino acid residues, and the y-axis shows the total number of patients with each pathogenic variant. HGVS.p of frequent variants with five or more patients are shown and four variants newly identified as pathogenic variants are underlined

Fig. 2

a Proportion of patients with pathogenic variants and b relative contribution of genes by the age at diagnosis of breast cancer women in 10-year-age groupings. a Proportion of patients with a pathogenic variant significantly decreased with advancing age (Cochran-Armitage test, P = 1.50 × 10⁻¹⁵). b Color indicates each gene as shown in the right legend