Abstract
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<1.0×10−5) 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.
Highlights
Breast cancer is the most common malignancy among women worldwide
We genotyped a total of 2,725 cases and 2,311 controls with Illumina OmniExpress BeadChip Kits that contained 733,202 SNPs to identify genetic variants associated with the susceptibility to breast cancer in the Japanese population
All the subjects participating in this study were clustered in the Asian population, there was a small portion of samples that were separated from the major Japanese (Hondo) cluster when principal component analysis (PCA) analysis was performed using only the genotype information of the case and control in the study (Figure S1a and S1b)
Summary
Breast cancer is the most common malignancy among women worldwide. In Japan, breast cancer comprises approximately 19% of all female cancers; it is the fifth leading cause of cancer death among women with an estimated death of 12,731 in 2011. Its incidence is about 86.0 cases/100,000 individuals/year and 56,289 were newly diagnosed to have breast cancer in 2007 (http://ganjoho.jp/data/public/statistics/backnumber/2012/files/ cancer_statistics_2012.pdf). Even though the 5-year survival rate for breast cancer is relatively better compared to other malignancies, the age-adjusted incidence and mortality rate for breast cancer has revealed a significant increase since 1970s in Japan. Breast cancer is one of the most important medical issues to be addressed. Individual risk assessment (genetic and environmental factors), early detection by biomarkers and mammography screening are critically important to reduce breast cancer-associated death
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