Diet and DNA methylation in colon mucosa and adenomas

饮食与结肠粘膜和腺瘤中的 DNA 甲基化

• 批准号: 6729543
• 负责人: Jean-Pierre J. Issa
• 金额: $ 28.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-13 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729543
• 关键词: CpG islands; DNA methylation; adenoma; aging; alcoholic beverage consumption; biopsy; cancer risk; clinical trials; colon; colorectal neoplasms; diet; dietary fiber; dietary lipid; dietary supplements; folate; gene environment interaction; genetic polymorphism; genetic susceptibility; genotype; human tissue; intestinal mucosa; neoplasm /cancer genetics; nutrition related neoplasm /cancer; nutrition related tag; nutritional epidemiology; patient oriented research; phenotype

DESCRIPTION (provided by applicant): DNA methylation within promoter-associated CpG islands marks and/or mediates epigenetic silencing in human cells. In normal colon, aberrant DNA methylation arises as a function of age and has been proposed as a mechanism contributing to age-related risk for colorectal tumors. Separately, a subset of colorectal tumors is characterized by intense hypermethylation of multiple genes, a process termed CpG Island Methylator Phenotype (CIMP). The factors that initiate and/or modulate age-related methylation and CIMP remain unknown. Based on preliminary data suggesting that dietary (fiber, folate) and/or lifestyle factors (alcohol, smoking) could modulate these processes, we propose the following hypotheses: (1) dietary factors influence the methylation status of genes in normal colon epithelium, (2) dietary factors influence the prevalence of CIMP in colorectal tumors and (3) Constitutive polymorphisms (MTHFR) modify the interactions between diet and hypermethylation in the colon. To test these hypotheses, we will use the unique resource of a wellcharacterized patient population enrolled in a trial of the prevention of colorectal adenomas by folate supplementation. Our specific aims are: (1) To determine associations between diet (folate, fiber, fat) and gene-specific DNA methylation (for multiple genes), as well as global DNA methylation (Alu methylation) in colon mucosa biopsies, controlling for MTHFR genotype, (2) to determine associations between diet (folate, fiber, fat) and CIMP status in colonic adenomas, controlling for MTHFR genotype and (3) to determine the effect of folate supplementation on DNA methylation (gene-specific and global) in colon mucosa and colon adenomas. These studies should provide definitive information on interactions between diet and DNA methylation in human colorectal mucosa and cancer.

描述（由申请人提供）： 与启动子相关的CpG岛中的DNA甲基化标记和/或介导人类细胞中的表观遗传沉默。在正常结肠中，异常的DNA甲基化是随着年龄的变化而产生的，并已被提出是有助于结直肠肿瘤风险的机制。另外，结直肠肿瘤的一个子集的特征是多个基因的强烈甲基化，该过程称为CpG岛甲基表型（CIMP）。引发和/或调节年龄相关的甲基化和CIMP的因素仍然未知。 Based on preliminary data suggesting that dietary (fiber, folate) and/or lifestyle factors (alcohol, smoking) could modulate these processes, we propose the following hypotheses: (1) dietary factors influence the methylation status of genes in normal colon epithelium, (2) dietary factors influence the prevalence of CIMP in colorectal tumors and (3) Constitutive polymorphisms (MTHFR) modify the interactions between diet和结肠中的高甲基化。为了检验这些假设，我们将使用良好的患者人群的独特资源，该患者人群通过补充叶酸来预防结直肠腺瘤的试验。我们的具体目的是：（1）确定饮食（叶酸，纤维，脂肪）与基因特异性DNA甲基化（用于多种基因）以及结肠粘膜活检中的全球DNA甲基化（ALU甲基化）之间的关联，以控制MTHFR基因组（2）的饮食（2）之间的饮食（2），以确定MTHFR基因组的相关性（2）。基因型和（3）确定叶酸补充对结肠粘膜和结肠腺瘤中DNA甲基化（基因特异性和全球）的影响。这些研究应提供有关人结直肠粘膜和癌症中饮食与DNA甲基化之间相互作用的明确信息。