The MTHFR C677T SNP exerts bipolar effects on colorectal cancer risk through the

MTHFR C677T SNP 通过以下方式对结直肠癌风险产生双极效应：

• 批准号: 7713460
• 负责人: JOEL B MASON
• 金额: $ 31.71万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7713460
• 关键词: Alleles; Amino Acid Substitution; Animal Model; Animals; Apoptosis; Biochemical; Cancer Burden; Carbon; Cell Cycle; Cell Cycle Kinetics; Clinical Research; Code; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Control Animal; DNA; DNA Methylation; Dietary Intervention; Disease; Engineering; Enzymatic Biochemistry; Enzymes; Epidemiologic Studies; Epithelium; Flavoproteins; Folate; Folic Acid; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Homozygote; Human; Human body; Individual; Inhibition of Apoptosis; Intake; Intestinal Neoplasms; Intestines; Knock-out; Laboratories; LacZ Genes; Maintenance; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolism; Methylenetetrahydrofolate reductase (NADPH); Micronutrients; Modeling; Molecular; Mouse Strains; Mus; Neoplastic Cell Transformation; Nutrient; Pathway interactions; Play; Population; Public Health; Reporter; Riboflavin; Risk; Risk Factors; Role; Science; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Societies; Staging; Supplementation; Testing; Translating; Translations; Uncertainty; Uracil; Variant; Vitamin B Complex; Vitamins; base; cancer risk; carcinogenesis; enzyme activity; fortification; gene interaction; genetic variant; in vivo; insight; interest; macromolecule; neoplastic; novel; nucleotide metabolism; pre-clinical; preclinical study; programs; public health relevance; research study; response; tumorigenesis

DESCRIPTION (provided by applicant): Over the past decade it has become abundantly clear that the highly prevalent C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene imparts substantial protection against the risk of developing colorectal cancer, and that its effect in this regard is a function of a nutrient-gene interaction with the B-vitamin, folate. Individuals who are homozygous for the variant and who are folate-replete enjoy a reduction in risk of 30-70% compared to wild-type individuals with comparable levels of folate, with diminishing degrees of protection among those whose folate status is less robust. Far less appreciated are the observations from both pre-clinical and clinical studies that indicate that the homozygote possesses an elevated risk when folate status is low. This bipolar effect of the C677T variant, whereby it conveys protection when folate status is adequate but conveys risk when folate status is low, is unique amongst all polymorphisms that play a role in determining cancer risk. Recent studies by my laboratory implicate the Wnt signaling pathway as playing a large role in the modulation of carcinogenesis mediated by folate and the other 1-carbon micronutrients. The purpose of the proposed animal studies is to conduct the initial steps necessary to define the mechanistic basis for this bipolar effect of the C677T variant. Unraveling the mechanistic basis of this effect will serve very important basic and applied functions. First, understanding the basis of the folate-C677T interaction will contribute critical insights into the related, but not identical, issue of how folate availability modulates colorectal cancer risk. From a public health perspective, a thorough appreciation for the underlying principles of how folate and this polymorphism conspire to modulate carcinogenesis is absolutely essential if industrialized societies are to intelligently and safely implement folic acid fortification programs, as well as identify appropriate individuals to target for supplementation programs that can reduce the burden of cancer. To accomplish these goals, two experiments will be conducted that collectively utilize three genetically- engineered strains of mice: one strain that is predisposed to intestinal carcinogenesis (Apc1638N); one strain that displays activity through the Wnt signaling cascade (BAT/lacZ); and one strain containing a cre-lox conditional knockout of the MTHFR gene that we recently created ourselves that models the human homozygous variant. The first experiment will determine whether the MTHFR knockout modulates early stages of colorectal carcinogenesis in a bipolar fashion depending on 1-carbon nutrient status, thereby establishing the relevance of this model to the human. The second experiment will then identify whether the nutrient-gene interaction modulates the Wnt pathway and its downstream effects on the cell cycle in a fashion that recapitulates its effects on carcinogenesis. PUBLIC HEALTH RELEVANCE: The purpose of the proposed animal studies is to define the mechanistic basis for the interaction between the common genetic variant, C677T, and the availability of folate and other related B-vitamins in determining the risk of colon cancer. Unraveling the mechanistic basis of this effect will serve very important basic and applied functions. First, understanding the basis of the folate-C677T interaction will contribute critical insights into the related, but not identical, issue of how folate availability modulates colorectal cancer risk. From a public health perspective, a thorough appreciation for the underlying principles of how folate and this polymorphism conspire to modulate carcinogenesis is absolutely essential if industrialized societies are to intelligently and safely implement folic acid fortification programs, as well as identify appropriate individuals to target for supplementation programs that can reduce the burden of cancer.

描述（由申请人提供）：在过去的十年中，已经很清楚地表明，高度普遍的C677T甲基烯烃还原性还原酶（MTHFR）基因具有实质性保护，可赋予对结直肠癌的风险进行实质性保护，并且其在这种方面的作用是与B-vit的营养相互作用的功能，是fceit b-vit的功能。与叶酸相当水平的野生型个体相比，对这种变体纯合的人的风险降低了30-70％，而叶酸状况较差的个体的保护程度降低。临床前和临床研究的观察结果表明，当叶酸状况较低时，纯合子的风险升高。 C677T变体的这种双极效应，当叶酸状况足够时，它传达了保护，但是当叶酸状况较低时会传达风险，在所有多态性中在确定癌症风险中发挥作用的所有多态性中都是独特的。我的实验室的最新研究暗示了Wnt信号通路是在叶酸和其他1碳微量营养素介导的致癌作用中起着重要作用。拟议的动物研究的目的是执行必要的初始步骤，以定义C677T变体这种双极效应的机械基础。阐明这种效果的机械基础将提供非常重要的基本和应用功能。首先，了解叶酸-C677T相互作用的基础将有助于对叶酸可用性调节结直肠癌风险的相关但不完全相同的问题。从公共卫生的角度来看，如果工业化社会要聪明，安全地实施叶酸酸性强化计划，以及确定可以减少癌症负担的补充计划，对叶酸和这种多态性如何调节癌变的基本原则是绝对必要的。为了实现这些目标，将进行两个实验，共同利用三种基因工程菌株的小鼠：一种易于肠道致癌作用的菌株（APC1638N）；一种通过Wnt信号级联（BAT/LACZ）显示活性的菌株；还有一种含有MTHFR基因的Cre-Lox条件敲除的菌株，我们最近创建了自己对人类纯合变量进行建模的菌株。第一个实验将确定MTHFR敲除是否根据1碳养分状态调节双极性癌变的早期阶段，从而确定该模型与人类的相关性。然后，第二个实验将确定营养基因相互作用是否会以一种概括其对癌变作用的方式调节Wnt途径及其对细胞周期的下游影响。公共卫生相关性：拟议的动物研究的目的是定义常见遗传变异，C677T之间相互作用的机理基础，以及叶酸和其他相关B-Vitamins在确定结肠癌风险方面的可用性。阐明这种效果的机械基础将提供非常重要的基本和应用功能。首先，了解叶酸-C677T相互作用的基础将有助于对叶酸可用性调节结直肠癌风险的相关但不完全相同的问题。从公共卫生的角度来看，如果工业化社会要聪明，安全地实施叶酸酸性强化计划，以及确定可以减少癌症负担的补充计划，对叶酸和这种多态性如何调节癌变的基本原则是绝对必要的。