Han Mi-Ryung, Zheng Wei, Cai Qiuyin, Gao Yu-Tang, Zheng Ying, Bolla Manjeet K, Michailidou Kyriaki, Dennis Joe, Wang Qin, Dunning Alison M, Brennan Paul, Chen Shou-Tung, Choi Ji-Yeob, Hartman Mikael, Ito Hidemi, Lophatananon Artitaya, Matsuo Keitaro, Miao Hui, Muir Kenneth, Sangrajrang Suleeporn, Shen Chen-Yang, Teo Soo Hwang, Tseng Chiu-Chen, Wu Anna H, Yip Cheng Har, Kang Daehee, Xiang Yong-Bing, Easton Douglas F, Shu Xiao-Ou, Long Jirong
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203,USA.
Department of Epidemiology, Shanghai Cancer Institute, Shanghai200032, China.
Carcinogenesis. 2017 May 1;38(5):511-518. doi: 10.1093/carcin/bgx010.
Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS). We found three missense variants with minor allele frequency (MAF) <0.05: rs80358978 (Gly2508Ser), rs80359065 (Lys2729Asn) and rs11571653 (Met784Val) in the BRCA2 gene, showing statistically significant associations with breast cancer risk, with P-values of 1.2 × 10-4, 1.0 × 10-3 and 5.0 × 10-3, respectively. In addition, we found four low-frequency variants (rs8176085, rs799923, rs8176173 and rs8176258) in the BRCA1 gene, one common variant in the CHEK2 gene (rs9620817), and one common variant in the PALB2 gene (rs13330119) associated with breast cancer risk at P < 0.01. Our study identified several new risk variants in BRCA1, BRCA2, CHEK2, and PALB2 genes in relation to breast cancer risk in Asian women. These results provide further insights that, in addition to the high/moderate penetrance mutations, other low-penetrance variants in these genes may also contribute to breast cancer risk.
在过去20年中，已鉴定出乳腺癌相关基因BRCA1、BRCA2、TP53、PTEN、STK11和CDH1中的高外显率致病突变，以及基因CHEK2、ATM、BRIP1、PALB2、RAD51C、RAD50和NBN中的中等外显率突变。在本研究中，我们调查了在亚洲血统女性中，这13个基因中是否存在与乳腺癌相关的其他变异。我们分析了乳腺癌协会联盟（BCAC）纳入的6269例亚洲血统病例和6624例对照中的多达654个单核苷酸多态性（SNP），以及上海乳腺癌遗传学研究（SBCGS）纳入的5794例病例和5529例对照中的多达236个SNP。我们在BRCA2基因中发现了三个次要等位基因频率（MAF）<0.05的错义变异：rs80358978（Gly2508Ser）、rs80359065（Lys2729Asn）和rs11571653（Met784Val），它们与乳腺癌风险显示出统计学上的显著关联，P值分别为1.2×10-4、1.0×10-3和5.0×10-3。此外，我们在BRCA1基因中发现了四个低频变异（rs8176085、rs799923、rs8176173和rs8176258），在CHEK2基因中发现了一个常见变异（rs9620817），在PALB2基因中发现了一个常见变异（rs13330119），它们与乳腺癌风险的关联在P<0.01水平上具有统计学意义。我们的研究确定了BRCA1、BRCA2、CHEK2和PALB2基因中与亚洲女性乳腺癌风险相关的几个新的风险变异。这些结果提供了进一步的见解，即除了高/中等外显率突变外，这些基因中的其他低外显率变异也可能导致乳腺癌风险。
