Folate, 1-Carbon Nutrients, Gene Variants & Colon Cancer

描述(由申请人提供)： 在研究膳食叶酸摄入量与结直肠癌发病风险之间关系的20多项流行病学研究中，大多数都报告了叶酸摄入量越高，罹患结直肠癌的风险越低。使用致癌物诱导的或基因工程的啮齿动物结直肠癌模型进行的动物研究表明，饮食中的叶酸与结直肠癌风险之间存在负相关关系。叶酸代谢途径影响基因组甲基化和DNA合成所需核苷酸的供应；这些也可能受到维生素B12、B6和B2供应充足的影响，这些都是该途径中关键酶反应的辅助因素。我们团队的总体长期目标是通过结合动物、机制、人类观察性研究和临床试验，确定叶酸和其他营养因素在结直肠癌一碳代谢中的作用。我们将通过建立一个研究叶酸、一碳营养物质、基因变异和结直肠癌的合作专门中心来实现这一目标。该中心将是位于波士顿的哈佛大学和塔夫茨大学、位于新汉普郡的达特茅斯大学、位于欧洲的国际癌症研究机构和卑尔根大学、位于波士顿的Variagenics公司以及美国国家癌症研究所癌症预防部门和癌症研究中心之间的合作项目。我们被组织成三个项目、发展项目和两个核心。 项目1将汇集来自三项大型前瞻性队列研究的数据，这些研究包含2,700例预期的结直肠癌病例，以确定更高的叶酸摄入量是否降低了结直肠癌的风险，并检查这种降低的风险在低蛋氨酸摄入量、低血浆叶酸、低维生素B12、B6和B2水平的人、每天喝一种以上酒精饮料的人、以及亚甲基四氢叶酸还原酶(MTHFR)C677T多态的纯合子和MTHFR A1298C多态的复合杂合子中是否更大。 项目2将验证结肠癌发生的小鼠模型，作为检查叶酸和其他一碳代谢贡献者改变风险的系统。 项目3将使用叶酸补充的两个随机临床试验的数据和样本，评估外周血淋巴细胞和远端结肠活检中尿嘧啶的误结合程度和基因组甲基化是否代表一碳营养充足和结直肠腺瘤风险的生物标志物。 这些项目将得到创新发展项目的支持。在最初的发育项目1中，带有MTHFR零等位基因和同源C677T多态的转基因小鼠；这些小鼠将被纳入项目2的喂养研究。在发展项目2中，我们将探索影响血浆叶酸和同型半胱氨酸水平的5个叶酸代谢基因的多态。 所有项目都将得到行政和统计核心(设在哈佛公共卫生学院)和测量核心(设在塔夫茨大学人类营养研究中心)的支持。 这些高度相关的研究将有助于整合流行病学和机械学观察，并有助于提供关于叶酸和B族维生素最佳摄入量的公共卫生建议的基础。

DESCRIPTION (provided by applicant): Most of the over twenty epidemiologic studies that have examined the relationship between dietary folate intake and the risk of developing colorectal neoplasms, have reported that higher folate intakes are associated with lower risk. Animal studies, using either carcinogen-induced or genetically engineered rodent models of colorectal cancer, have indicated an inverse relationship between dietary folate and the risk of colorectal cancer. The folate metabolic pathway influences genomic methylation and the supply of nucleotides for DNA synthesis; these can also be influenced by adequacy of supply of vitamins B12, B6, and B2, all co-factors for critical enzymatic reactions in the pathway. The overall long-term objective of our Team is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. We will accomplish this by establishing a Cooperative Specialized Center for the study of Folate, One carbon nutrients, Gene variants and Colorectal cancer. This Center will be a Collaborative Program between Harvard and Tufts Universities in Boston, Dartmouth University in New Hampshire, the International Agency for Research in Cancer and the University of Bergen in Europe, Variagenics Inc. in Boston, and the Division of Cancer Prevention and the Center for Cancer Research at the NCI. We are organized into three projects, developmental projects, and two cores. Project 1 will pool data from three large prospective cohort studies with 2,700 expected colorectal cancer cases to establish whether higher intake of folic acid reduces risk of colorectal cancer and examine whether this reduced risk is greater among persons with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and homozygotes for the methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism, and compound heterozygotes for the MTHFR A1298C polymorphism. Project 2 will validate mouse models of colon carcinogenesis as systems to examine modification of risk by folate and other contributors to one-carbon metabolism. Project 3 will assess whether the degree of uracil misincorporation and genomic methylation in peripheral blood lymphocytes and distal colon biopsies represent biomarkers of one-carbon nutrient adequacy and colorectal adenoma risk, using data and samples from two randomized clinical trials of folate supplementation. The projects will be supported by innovative Developmental Projects. In initial Developmental Project 1 transgenic mice with the null allele of MTHFR, and the homologous C677T polymorphism; these mice will be available for incorporation into feeding studies in Project 2. In Developmental Project 2 we will explore five folate-metabolism genes for polymorphisms that influence plasma folate and homocysteine levels. All Projects will be supported by the Administrative and Statistical Core (based at the Harvard School of Public Health), and the Measurement Core (based at the Human Nutrition Research Center at Tufts University). These highly interrelated studies will help integrate epidemiologic and mechanistic observations and help provide a basis for public health recommendations on optimal levels of folate and B vitamin intake.