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表现。异常调节的表观遗传变化通常以异常DNA甲基化模式为代表，如整体低甲基化和区域特异性高甲基化，是大多数癌症（包括乳腺癌）的标志。虽然甲基化模式改变的确切机制还远未完全，但总体甲基化过程主要由一组调节蛋白调节，包括DNA甲基转移酶（DNMT）和甲基胞嘧啶鸟嘌呤二核苷酸（CpG）结合蛋白（MBD）。在这个提议中，我们假设与甲基化相关基因相关的不良基因型可能会调节其蛋白质在表观遗传调控中的功能，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）确定单核苷酸多态性（SNPs）的甲基化相关基因的潜在功能的影响。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SNP和位于外显子剪接位点的SNP进行关于功能影响的预测。2)确定这些基因的特定多态性在乳腺癌风险调节中的作用。我们的假设是，预测在甲基化过程中具有功能意义的SNPs可能是与乳腺癌风险相关的一组生物标志物。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，暴露于吸烟，饮酒和环境雌激素可能会改变乳腺癌的风险与甲基化相关基因的推定高风险基因型的个人。鉴于可以获得DNA样本和接触数据，就实际可行性而言，这一建议既节省时间又节省成本。

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.