Methylation Related Genes and Breast Cancer Risk

描述(由申请人提供)： 癌症最近被认为是异常遗传和表观遗传事件的一种表现。异常的表观遗传学变化通常表现为异常的DNA甲基化模式，如全局低甲基化和区域特异性高甲基化，是包括乳腺癌在内的大多数癌症的特征。虽然甲基化模式改变的确切机制还不完全，但整个甲基化过程主要受一组调节蛋白的调控，包括DNA甲基转移酶(DNMT)和甲基胞嘧啶鸟嘌呤二核苷酸结合蛋白(MBDS)。在这一建议中，我们假设与甲基化相关基因相关的不利基因类型可能在表观遗传调节中调节其蛋白质功能，从而影响个体对人类乳腺癌的易感性。我们的具体目标是：1)确定对甲基化相关基因具有潜在功能影响的单核苷酸多态(SNPs)。SNP将从公共SNP数据库中收集，并通过不同的生物信息学工具进行筛选。将对改变氨基酸的SNPs和位于外显子剪接点的SNPs的功能影响进行预测。2)确定这些基因的特定多态在乳腺癌风险调控中的作用。我们的假设是，被预测在甲基化过程中具有功能意义的SNPs可能是一组与乳腺癌风险相关的生物标记物。3)探讨甲基化相关基因与环境因素的联合作用。我们的假设是，吸烟、饮酒和环境雌激素的暴露可能会改变甲基化相关基因中假定的高危基因类型的个体患乳腺癌的风险。考虑到DNA样本和暴露数据的可用性，就实际可行性而言，这项建议既有时间效益，又有成本效益。

DESCRIPTION (provided by applicant): Cancer has been recently recognized as a manifestation of both abnormal genetic and epigenetic events. Dysregulated epigenetic changes usually represented by abnormal DNA methylation patterns, such as global hypomethylation and region-specific hypermethylation, are a hallmark of most cancers, including breast cancer. Although the precise mechanisms underlying alterations of methylation patterns are far from complete, the overall methylation process is mainly regulated by a group of regulatory proteins including DNA methyltransferases (DNMTs) and methyl-cytosine guanine dinucleotide (CpG) binding proteins (MBDs). In this proposal, we hypothesize that adverse genotypes associated with methylation related genes may modulate their protein functions in epigenetic regulation, thereby influencing individual's susceptibility to human breast cancer. Our specific aims are: 1) To identify single nucleotide polymorphisms (SNPs) with potential functional impact on methylation related genes. SNPs will be collected from public SNP databases and screened by different bioinformatic tools. Prediction about functional impact will be made to both SNPs that alter an amino acid and SNPs located in the exonic splicing sites. 2) To determine the role that specific polymorphisms in these genes playin the modulation of breast cancer risk. Our hypothesis is that SNPs predicted to have functional significance in methylation process may be a panel of biomarkers to be associated with breast cancer risk. 3) To investigate the joint-effect between methylation related genes and environmental factors. Our hypothesis is that exposure to tobacco smoking, alcohol consumption and environmental estrogens may modify the risk of breast cancer for individuals with the putative high-risk genotypes in methylation related genes. Given the availability of DNA samples and exposure data, this proposal is both time and cost effective in terms of practical feasibility.