Methylation Related Genes and Breast Cancer Risk

甲基化相关基因和乳腺癌风险

• 批准号: 6860132
• 负责人: YONG ZHU
• 金额: $ 8.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6860132
• 关键词: DNA methylation; alcoholic beverage consumption; bioinformatics; biomarker; breast neoplasms; cancer risk; computational biology; disease /disorder etiology; estrogens; female; gene environment interaction; genetic regulation; genetic screening; genetic susceptibility; genotype; human data; human tissue; methylation; molecular biology information system; neoplasm /cancer genetics; patient oriented research; protein structure function; single nucleotide polymorphism; smoking; tobacco abuse

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.

描述（由申请人提供）： 最近，癌症被认为是异常遗传和表观遗传事件的表现。通常由异常DNA甲基化模式（例如全球甲基化和特定区域特异性高甲基化）表示的表观遗传变化是大多数癌症的标志，包括乳腺癌。尽管甲基化模式的基础改变的确切机制远非完整，但总体甲基化过程主要受一组调节蛋白（包括DNA甲基转移酶（DNMT）（DNMT）和甲基 - 甲基 - 甲烷三核苷酸（CPG）结合蛋白（MBD）的调节蛋白（MBD）。在此提案中，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在表观遗传调节中的蛋白质功能，从而影响个人对人乳腺癌的敏感性。我们的具体目的是：1）鉴定具有潜在功能对甲基化相关基因的潜在功能影响的单核苷酸多态性（SNP）。 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。将对位于外显着剪接位点的氨基酸和SNP的两个SNP进行有关功能影响的预测。 2）确定在这些基因中特异性多态性在乳腺癌风险调节中的作用。我们的假设是，被预测在甲基化过程中具有功能意义的SNP可能是与乳腺癌风险相关的生物标志物。 3）研究相关基因与环境因素之间的联合效应。我们的假设是，暴露于吸烟，饮酒和环境雌激素可能会改变甲基化基因中假定高风险基因型的个体患乳腺癌的风险。鉴于DNA样品的可用性和暴露数据，该建议在实际可行性方面既是时间又是成本效益。