染色体19p13.1区域位点与中国女性三阴乳腺癌遗传易感性的研究

Breast cancer is a heterogeneous disease that can be divided into distinct subtypes including triple-negative. Triple-negative breast cancer (TNBC) related to poor prognosis has emerged as being of particular clinical and public health significance disease. Recently, A GWAS among European Caucasians has found that 19p13.1 is a TNBC susceptibility locus. It provides further evidence that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. However, there is a big difference in genetic structure, incidence and environmental among different races, and it is still unclear for the association between 19p13.1 and risk of TNBC in Chinese women. Therefore, it is very necessary to identify the genetic locus of 19p13.1 associated with TNBC among Chinese women. Based on Asian breast cancer GWAS, our group will firstly conduct a case-control study comprising 1000 TNBC cases and 1000 healthy controls to make fine mapping and scanning 19p13.1 locus in Chinese women. We will screen the specific SNPs associated with TNBC among Chinese women, as well as to explore the association of the region's SNPs and prognosis of TNBC. Then, we will make the validation in another 1000 TNBC cases and 1000 healthy controls to confirm the significant SNPs associated with TNBC risk. Our results will provide important evidences to demonstrate the difference of the potential genetic locus of 19p13.1 associated with TNBC in the different races. In addition, we will analyze interactions of SNP-SNP and gene-environment, which will provide valuable etiology clues to TNBC and important basis to the further functional study and new biomarker's discovery.

三阴乳腺癌是一类具有明显病因异质性的乳腺癌亚型，因缺乏有效的治疗手段预后较差，目前已成为具有重要临床和公共卫生意义的疾病。最近欧洲白人的GWAS研究发现19p13.1是三阴乳腺癌的易感区域，可能通过不同病因途径而起作用。然而，不同人种的遗传结构、发病率和环境暴露等因素存在较大差异，该易感区域与中国女性三阴乳腺癌的关系尚不清楚。本课题组拟在前期开展的亚洲乳腺癌GWAS研究基础上，首次在中国女性中开展1000对三阴乳腺癌病例对照研究，对染色体19p13.1区域进行精细定位扫描，进一步识别该区域国人特异的病因位点，探索该区域SNPs与三阴乳腺癌预后的关系。研究结果将在另外1000对独立人群验证，比较中国女性与欧洲白人易感位点的差异，论证该区域三阴乳腺癌易感位点在不同人种的作用，分析SNP之间以及SNP与环境因素的交互作用，为三阴乳腺癌的病因学研究、SNP功能验证和探索新的分子标志物提供重要依据。

三阴乳腺癌是一类具有明显病因异质性的乳腺癌亚型，可能出现通过不同的病因途径而起作用。由于不同人种的遗传结构，发病率，环境暴露等均存在较大差异，因此在中国人群中进行三阴乳腺癌易感性的研究，进一步识别和确定的国人病因位点，探索影响三阴乳腺癌遗传以及为未来开展功能的研究均是非常重要而且有意义的工作。近期国外GWAS研究在欧洲白人中发现19p13.1是三阴乳腺癌的易感区域，但该易感区域与中国女性三阴乳腺癌的关系尚不清楚。本研究利用Sequenom MassARRAY平台检测1000对中国三阴乳腺癌病例和健康对照中染色体19p13.1中200kb区域中所选出的28个tagSNP的基因型频率，进一步识别该区域国人特异的易感位点，分析SNP与环境因素的交互作用。结果显示:我们发现OCEL1基因rs2288542 位点频率分布与中国女性三阴乳腺癌发病风险显著相关，“C”等位基因型显著增加三阴乳腺癌发病风险（OR：1.576，95%CI:1.353-1.835)。同时我们在与环境交互作用分析中发现，与经常锻炼的妇女相比，携带rs2288542中“C”等位基因型的不经常体育锻炼妇女发生三阴乳腺癌风险更高，具有明显交互作用，为进一步的病因学解释提供了宝贵线索，也为下一步探索三阴乳腺癌的病因学研究、SNP功能验证和新的分子标志物提供重要依据。

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