DNA METHYLATION AND COLORECTAL POLYPS

描述：（改编自申请人的摘要）：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学中的作用， 腺瘤，并评估潜在的风险因素，从头甲基化， 腺瘤我们建议通过添加甲基化来实现我们的目标。 一项现有的基于乙状结肠镜检查的病例对照研究， 大肠腺瘤性息肉的环境和遗传危险因素 肠道将有1,000例和1,000例对照，食物频率和 风险因素问卷，空腹血液样本，以及病例病理学 报告和肿瘤块。我们提出以下目标： 首先，我们将对五个基因组中的从头甲基化进行描述性研究。 特异性基因，三种已知的肿瘤抑制基因（APC、hMLH 1和p16） 参与结直肠癌的启动子区域的高甲基化， 雌激素受体（ER），可能直接参与或不参与 结肠直肠息肉的病因，和一个“对照”基因，MYOD，这显然不是 与结直肠癌有关其次，我们将评估两个假设， 高甲基化的危险因素。第一种是饮食或红细胞减少 叶酸会增加高甲基化的发生率 ER的启动子区域。作为这个假设的一部分，我们将评估 通过基因修饰叶酸-甲基化关系， 亚甲基四氢叶酸还原酶（MTHFR），参与叶酸 新陈代谢.第二个假设是，使用绝经后激素将 与雌激素受体高甲基化发生率较低有关。三是 将确定是否有差异的甲基化状态的五个 比较了具有复制错误表型（RER+）的腺瘤中的靶基因 没有这种表型的腺瘤（RER-）。我们建议测量甲基化 状态与一个新的程序（COBRA），由彼得·莱尔德博士开发， 灵敏度和定量性优于其他检测方法， 石蜡包埋组织的大样本将该测定与我们的 正在进行的研究将为我们提供一个强有力的手段， 关于甲基化及其在癌症中的作用。我们建议测量 甲基化状态与新的程序（COBRA），由彼得·莱尔德博士开发， 其比我们正在进行研究中的其它测定法更灵敏和定量 将提供一个强有力的手段来解决重要的问题， 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.