Abstract 2780: Evaluation of genetic variants in high and moderate-penetrance breast cancer susceptibility genes in East Asians
Authors: Han Mi-Ryung , Shu Xiao-Ou , Cai Qiuyin , Gao Yu-Tang , Zheng Ying , Michailidou Kyriaki , Dennis Joe , Bolla Manjeet K. , Wang Qin , Choi Ji-Yeob , Hartman Mikael , Kang Daehee , Lophatananon Artitaya , Miao Hui , Matsuo Keitaro , Muir Kenneth , Sangrajrang Sulee , Shen Chen-Yang , Teo Soo Hwang , Wu Anna H , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Zheng Wei , Long Jirong 
Published: August 2015

Abstract
Breast cancer is the most common invasive cancer in females worldwide. Over the past 20 years, pathogenic mutations in high-penetrance genes (BRCA1, BRCA2, PTEN and TP3) and moderate-penetrance genes (CHEK2, ATM, BRIP1, PALB2, RAD51C, STK11, CDH1, RAD50, and NBN) have been identified for breast cancer. Most of these germline mutations were discovered in women of European ancestry. In the present study, we aimed to investigate whether there were additional variants in these genes associated with breast cancer among women of Asian ancestry. Genotype data of up to 584 SNPs from the Breast Cancer Association Consortium (BCAC) including 6,269 cases and 6,624 controls and Shanghai Breast Cancer Genetics Study (SBCGS) including 5,768 cases and 5,703 controls were analyzed. Among 18 reported pathogenic mutations included in the dataset, 12 were monomorphic. Rare allele was observed for the remaining 6 mutations and one of them showed a significant association with P value of 0.0096. Among the remaining SNPs that were not previously reported to be pathogenic, 17 SNPs showed nominal association with P&lt;0.05 in the Asian populations. Notably, SNP rs80359065 in the BRCA2 gene showed significant association with OR (95% CI) of 1.46 (1.15-1.84) and P value of 1.8 × 10−3 in the BCAC, and OR (95% CI) of 1.14 (1.03-1.27) and P value of 1.3 × 10−2 in the SBCGS. In the combined data, the OR (95% CI) was 1.23 (1.13-1.32) and the P value reached 7.0 × 10−5, lower than the bonferroni corrected P value (9.1 × 10−5). This SNP has a minor allele frequency (MAF) of 1% in the present study, more prevalent than reported pathogenic mutations. Another variant in the BRCA2 gene, rs80358978, was also associated with breast cancer with P value of 5.8 × 10−3 in the combined dataset. In the BRCA1 gene, three low-frequency variants with MAF&lt;0.1% were associated with breast cancer, including rs8176085, rs799923, and rs1799950 with P values of 8.7 × 10−4, 1.0 × 10−3, and 5.8 × 10−3, respectively. Two common variants with MAF&gt;10% in the RAD50 gene were also associated with breast cancer with P value of 1.0 × 10−3 and 2.1 × 10−3 for rs17772583 and rs2244012, respectively. Our study identified several new risk variants in the BRCA1, BRCA2 and RAD50 genes in relation to breast cancer risk in East Asian women and showed that many of the previously reported pathogenic mutations in the high/moderate penetrance genes of breast cancer are rare in our study population comprising largely sporadic breast cancer patients of East Asian ancestry.
Citation Format: Mi-Ryung Han, Xiao-Ou Shu, Qiuyin Cai, Yu-Tang Gao, Ying Zheng, Kyriaki Michailidou, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ji-Yeob Choi, Mikael Hartman, Daehee Kang, Artitaya Lophatananon, Hui Miao, Keitaro Matsuo, Kenneth Muir, Sulee Sangrajrang, Chen-Yang Shen, Soo Hwang Teo, Anna H Wu, Alison M. Dunning, Paul D. P. Pharoah, Douglas F. Easton, Wei Zheng, Jirong Long. Evaluation of genetic variants in high and moderate-penetrance breast cancer susceptibility genes in East Asians. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2780. doi:10.1158/1538-7445.AM2015-2780