TGF-Beta/Smads信号通路调控基因多态性与乳腺癌遗传易感性及其机制研究

项目名称： TGF-Beta/Smads信号通路调控基因多态性与乳腺癌遗传易感性及其机制研究

项目编号： No.81672790

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 田新霞

作者单位： 北京大学

项目金额： 25万元

中文摘要： TGF-β/Smads信号通路异常与乳腺癌发生与发展密切相关。国内外研究人员通过候选基因策略及候选信号通路策略，发现TGF-β/Smads信号通路调控基因的遗传多态性可以影响乳腺癌的易感性。但是，对于易感SNP位点所在区域的功能性位点及作用机制尚不清楚。我们前期对TGFB1基因5’端调控区的多态性研究发现：SNP rs1800469（C>T）、Indel rs11466313（AGG/Del）次要等位基因携带者，发生乳腺癌的风险分别降低24%和32%；单体型Del-T携带者，发生乳腺癌的风险降低69%；生物信息学提示rs11466313（AGG/Del）很可能是一个功能性位点。本课题拟通过病例-对照分析、精细定位等方法，确定TGF-β/Smads信号通路调控基因中,与乳腺癌发生风险关联性较强的3--5个功能性变异位点，并进行深入机制探讨，为乳腺癌的风险预测提供理论依据。

中文关键词： C21_乳腺肿瘤；TGF-β/Smads；单核苷酸多态性；插入/缺失多态；易感性

英文摘要： Defect or deficiency in the TGF-β/Smads pathway has been proved to be closely associated with the occurrence of breast cancer. Researchers both in China and abroad, using candidate gene approach and candidate signal pathway approach, found that genetic polymorphisms of the TGF-β/Smads pathway’s regulatory genes can affect susceptibility to breast cancer. However, the functional loci in the area of the SNPs are yet to be found, and their mechanisms still elude us. Our prior research in the polymorphisms of the regulatory sequence of the 5’ terminal of TGFB1 showed a decline in risk of breast cancer by 24% and 32% respectively when carrying a minor loci of SNP rs1800469 (C>T) or Indel rs11466313 (AGG/Del); Carriers of the haplotype Del-T have their risk of breast cancer reduced by 69%; Bioinformatics suggest that rs11466313 (AGG/Del) may very likely be a functional loci, but its mechanisms require further research. Our project here proposes a plan using a series of methods such as case-control study and precise positioning to determine 3--5 potential functional loci, and explore their mechanism to affect susceptibility of breast cancer, in the hope that it might help provide theoretical support for assessment and prediction of breast cancer risk.

英文关键词： breast cancer;TGF-β/Smads;SNP ;Indel;susceptibility