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)：在过去的十年里，非常明显的是，亚甲基四氢叶酸还原酶(MTHFR)基因的高度流行的C677T多态可以提供实质性的保护，防止发生结直肠癌的风险，并且它在这方面的效果是营养-基因与B-维生素叶酸相互作用的功能。与叶酸水平相当的野生型个体相比，变异纯合子和叶酸充足的个体风险降低30%-70%，叶酸状况不那么强健的人的保护程度降低。从临床前和临床研究中观察到的结果表明，当叶酸水平较低时，纯合子具有更高的风险，这一点远未得到重视。C677T变异体的这种双极效应，在叶酸状态充足时提供保护，但在叶酸状态低时传递风险，在所有决定癌症风险的基因多态中是独一无二的。我的实验室最近的研究表明，Wnt信号通路在叶酸和其他1-碳微量营养素介导的致癌过程中发挥着重要作用。拟议的动物研究的目的是进行必要的初始步骤，以确定C677T变异的这种双极效应的机制基础。解开这一效应的机制基础，将具有十分重要的基础和应用作用。首先，了解叶酸-C677T相互作用的基础将有助于对叶酸可获得性如何调节结直肠癌风险这一相关但不相同的问题提供关键的见解。从公共卫生的角度来看，如果工业化社会要明智和安全地实施叶酸强化计划，并确定适当的个人作为补充计划的目标，以减轻癌症负担，彻底了解叶酸和这种多态如何共同调控癌症发生的基本原理是绝对必要的。为了实现这些目标，将进行两个实验，共同利用三个转基因小鼠品系：一个是易于发生肠癌的品系(Apc1638N)；一个是通过Wnt信号级联反应显示活性的品系(BAT/LacZ)；以及一个包含我们自己最近创建的模拟人类纯合变体的MTHFR基因的cre-lox条件性敲除的品系。第一个实验将确定MTHFR基因敲除是否以一种依赖于1-碳营养状态的两极方式调节结直肠癌发生的早期阶段，从而建立这一模型与人类的相关性。第二个实验将确定营养-基因相互作用是否以一种概括其对癌症发生的影响的方式来调节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确定常见基因变体C677T与叶酸和其他相关B族维生素的可用性之间相互作用的机制基础，以确定结肠癌的风险。解开这一效应的机制基础，将具有十分重要的基础和应用作用。首先，了解叶酸-C677T相互作用的基础将有助于对叶酸可获得性如何调节结直肠癌风险这一相关但不相同的问题提供关键的见解。从公共卫生的角度来看，如果工业化社会要明智和安全地实施叶酸强化计划，并确定适当的个人作为补充计划的目标，以减轻癌症负担，彻底了解叶酸和这种多态如何共同调控癌症发生的基本原理是绝对必要的。