Diet and DNA methylation in colon mucosa and adenomas

描述（由申请人提供）： 启动子相关CpG岛内的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DNA甲基化作为年龄的函数而出现，并且已被提出作为促成结直肠肿瘤的年龄相关风险的机制。另外，一个亚组的结直肠肿瘤的特征是多个基因的高度甲基化，这一过程称为CpG岛甲基化表型（CIMP）。启动和/或调节年龄相关甲基化和CIMP的因素仍然未知。根据初步数据显示，（纤维，叶酸）和/或生活方式因素（酒精，吸烟）可以调节这些过程，我们提出以下假设：（1）饮食因素影响正常结肠上皮中基因的甲基化状态，（2）饮食因素影响CIMP在结直肠肿瘤中的患病率;（3）组成型多态性（MTHFR）改变饮食和结肠中高甲基化之间的相互作用。为了验证这些假设，我们将使用一个独特的资源，一个特征良好的患者群体参加了一项试验，预防结直肠腺瘤的叶酸补充剂。我们的具体目标是：（1）确定饮食之间的关联（叶酸、纤维、脂肪）和基因特异性DNA甲基化（对于多个基因），以及全局DNA甲基化（2）在控制MTHFR基因型的情况下，在结肠粘膜活检中检测Alu甲基化，以确定饮食与（叶酸，纤维，脂肪）和CIMP状态在结肠腺瘤，控制MTHFR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（基因特异性和整体）的影响。这些研究应该提供明确的信息之间的相互作用，饮食和DNA甲基化在人类结直肠粘膜和癌症。

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.