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

描述（由申请人提供）： 在20多项流行病学研究中，大多数研究都研究了膳食叶酸摄入量与结直肠肿瘤风险之间的关系，并报告了较高的叶酸摄入量与较低的风险相关。使用致癌物诱导的或基因工程的结直肠癌啮齿动物模型进行的动物研究表明，膳食叶酸与结直肠癌风险之间存在反比关系。叶酸代谢途径影响基因组甲基化和DNA合成所需的核苷酸供应;这些也可能受到维生素B12、B6和B2供应充足的影响，这些都是途径中关键酶促反应的辅助因子。我们团队的总体长期目标是通过结合动物，机制，人体观察性研究和临床试验，确定叶酸和其他营养成分对结直肠癌中一碳代谢的作用。我们将通过建立一个专门的合作中心来研究叶酸，一碳营养素，基因变异和结直肠癌。该中心将是波士顿的哈佛大学和塔夫茨大学、新罕布什尔州的达特茅斯大学、国际癌症研究机构和欧洲的卑尔根大学、Variagenics Inc.以及NCI的癌症预防部门和癌症研究中心。我们分为三个项目，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，其中包括2，700例预期的结直肠癌病例，以确定叶酸摄入量增加是否会降低结直肠癌的风险，并检查这种降低的风险是否在蛋氨酸摄入量低，血浆叶酸水平低，维生素B12，B6和B2水平低，每天饮用一种以上酒精饮料的人群中更大，和亚甲基四氢叶酸还原酶（MTHFR）C677 T多态性的纯合子，以及MTHFR A1298 C多态性的复合杂合子。 项目2将验证结肠癌发生的小鼠模型作为系统，以检查叶酸和其他一碳代谢贡献者的风险修改。 项目3将评估外周血淋巴细胞和远端结肠活检中尿嘧啶错误掺入和基因组甲基化的程度是否代表一碳营养充足和结直肠腺瘤风险的生物标志物，使用来自两项叶酸补充剂随机临床试验的数据和样本。 这些项目将得到创新发展项目的支持。在初始开发项目1中，具有MTHFR无效等位基因和同源C677 T多态性的转基因小鼠;这些小鼠将可用于项目2的饲养研究。在发展项目2中，我们将探讨五个叶酸代谢基因的多态性影响血浆叶酸和同型半胱氨酸水平。 所有项目都将得到行政和统计核心（位于哈佛公共卫生学院）和测量核心（位于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制观察，并有助于为叶酸和B族维生素摄入量的最佳水平提供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.