Genome-Wide Association Study of Breast Cancer in the Japanese Population

Breast cancer is the most common malignancy among women in worldwide including Japan. Several studies have identified common genetic variants to be associated with the risk of breast cancer. Due to the complex linkage disequilibrium structure and various environmental exposures in different populations, it is essential to identify variants associated with breast cancer in each population, which subsequently facilitate the better understanding of mammary carcinogenesis. In this study, we conducted a genome-wide association study (GWAS) as well as whole-genome imputation with 2,642 cases and 2,099 unaffected female controls. We further examined 13 suggestive loci (P−5) using an independent sample set of 2,885 cases and 3,395 controls and successfully validated two previously-reported loci, rs2981578 (combined P-value of 1.31×10−12, OR = 1.23; 95% CI = 1.16–.30) on chromosome 10q26 (FGFR2), rs3803662 (combined P-value of 2.79×10−11, OR = 1.21; 95% CI = 1.15–.28) and rs12922061 (combined P-value of 3.97×10−10, OR = 1.23; 95% CI = 1.15–.31) on chromosome 16q12 (TOX3-LOC643714). Weighted genetic risk score on the basis of three significantly associated variants and two previously reported breast cancer associated loci in East Asian population revealed that individuals who carry the most risk alleles in category 5 have 2.2 times higher risk of developing breast cancer in the Japanese population than those who carry the least risk alleles in reference category 1. Although we could not identify additional loci associated with breast cancer, our study utilized one of the largest sample sizes reported to date, and provided genetic status that represent the Japanese population. Further local and international collaborative study is essential to identify additional genetic variants that could lead to a better, accurate prediction for breast cancer.</p

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

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

Identification of two novel breast cancer loci through large-scale genome-wide association study in the Japanese population

Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10−8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population