DNA METHYLATION AND COLORECTAL POLYPS

描述：(改编自申请者摘要)：我们的总体目标是 为了更好地确定DNA甲基化在结直肠癌病因中的作用 腺瘤，并评估潜在的危险因素去新甲基化。 腺瘤。我们建议通过添加甲基化来实现我们的目标 一项基于乙状结肠镜检查的病例对照研究 大腺瘤性息肉的环境和遗传危险因素 肠道将有1,000个病例和1,000个对照，食物频率和 风险因素问卷，空腹血样，以及病例的病理 报告和肿瘤块。我们提出以下目标： 首先，我们将对五年中的从头甲基化进行描述性研究 特异性基因，三个已知的肿瘤抑制基因(apc、hMLH1和p16) 参与结直肠癌启动子区高甲基化的癌 雌激素受体(ER)，它可能直接也可能不直接参与 大肠息肉的病因学，以及一个明显不是 与结直肠癌有关。第二，我们将评估关于以下两个假设 高甲基化的危险因素。第一个是饮食或红细胞减少 叶酸将与高甲基化患病率增加有关 内质网的启动子区域。作为这一假设的一部分，我们将评估 叶酸-甲基化关系的基因修饰， 亚甲基四氢叶酸还原酶(MTHFR)，与叶酸有关 新陈代谢。第二个假设是绝经后激素的使用将 与较低的ER高甲基化患病率有关。第三，我们 将确定这五种基因的甲基化状态是否存在差异 复制错误表型(RER+)与腺瘤靶基因的比较 无该表型的腺瘤(RER-)。我们建议测量甲基化 彼得·莱尔德博士开发的一种新程序(COBRA)的状况，更多 比其他可行的检测方法更灵敏和定量 一大块石蜡包埋的组织样本。把这项化验和我们的 正在进行的研究将为我们提供一个强大的手段来解决重要的 关于甲基化及其在癌症中的作用的问题。我们建议测量 由Peter Laird博士开发的一种新程序(COBRA)的甲基化状态， 这比我们正在进行的研究中的其他分析更灵敏和定量 将提供一种强大的方法来解决以下重要问题 甲基化及其在癌症病因学中的作用。

DESCRIPTION: (Adapted from the Applicant's Abstract): Our overall objective is to better define the role DNA methylation in the etiology of colorectal adenomas, and to assess potential risk factors for de novo methylation in adenomas. We propose to accomplish our objective by adding a methylation component onto an existing sigmoidoscopy-based case-control study of environmental and genetic risk factors for adenomatous polyps of the large bowel that will have 1,000 cases and 1,000 controls, with food frequency and risk factors questionnaires, a fasting blood sample, and, for cases, pathology reports and tumor blocks. We propose the following aims: First, we will conduct a descriptive study of de novo methylation in five specific genes, three known tumor suppressor genes (APC, hMLH1, and p16) involved in colorectal of hypermethylation of the promoter region cancer, the estrogen receptor (ER), which may or may not be directly involved in the etiology of colorectal polyps, and a "control" gene, MYOD, that is clearly not involved in colorectal cancer. Second, we will assess two hypotheses regarding risk factors for hypermethylation. The first is that decreased dietary or RBC folic acid will be associated with an increase prevalence of hypermethylation of the promoter region of the ER. As part of this hypothesis, we will assess modification of the folic acid-methylation relationship by a gene, methylene-tetrahydrofolate reductase (MTHFR), that is involved in folic acid metabolism. The second hypothesis is that use of postmenopausal hormones will be associated with a lower prevalence of hypermethylation of the ER. Third, we will determine if there are differences in the methylation status of the five target genes in adenomas with the replication error phenotype (RER+) compared to adenomas without that phenotype (RER-). We propose to measure methylation status with a new procedure (COBRA), developed by Dr. Peter Laird , that more sensitive and quantitative than other assays that can feasibly be conducted on a large sampled of paraffin-embedded tissue. Combining this assay with our ongoing study will provide us with a powerful means of addressing important questions about methylation and its role on cancer. We propose to measure methylation status with a new procedure (COBRA), developed by Dr. Peter Laird, that is more sensitive and quantitative than other assay with our ongoing study will provide a powerful means of addressing important questions about methylation and its role on cancer etiology.