Dietary Methyl Score, Genomic DNA Methylation and Colorectal Cancer

膳食甲基评分、基因组 DNA 甲基化与结直肠癌

• 批准号: 8267118
• 负责人: EUNYOUNG CHO
• 金额: $ 32.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267118
• 关键词: Address; Affect; Alcohols; Animals; Attenuated; Betaine; Biochemical Genetics; Biochemical Reaction; Biological; Biological Assay; Blood; Blood specimen; Body measure procedure; Carbon; Characteristics; Choline; Code; Colon; Colon Carcinoma; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; CpG Island Methylator Phenotype; Critical Pathways; Cross-Sectional Studies; Cysteine; DNA; DNA Maintenance; DNA Methylation; DNA Repair; DNA biosynthesis; Data; Databases; Development; Diagnostic; Diet; Dietary Assessment; Dietary Factors; Enzymes; Epigenetic Process; Equilibrium; Family; Family history of; Fibrinogen; Folate; Folic Acid; Food; Genes; Genetic Polymorphism; Genomics; Genotype; Guidelines; Health Professional; Homocysteine; Homocystine; Human; Individual; Intake; Knowledge; Lead; Leukocytes; Long Interspersed Nucleotide Elements; Lymphocyte; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolism; Methionine; Methylation; Methylenetetrahydrofolate reductase (NADPH); Microsatellite Instability; Molecular; Mus; Neoplasms; Nucleotide Biosynthesis; Nurses' Health Study; Nutrient; Pathway interactions; Plasma; Play; Positioning Attribute; Prospective Studies; RNA; Recording of previous events; Relative (related person); Research; Riboflavin; Risk; Role; Screening for cancer; Specimen; Stress; Surrogate Markers; Tetrahydrofolates; Time; Variant; Vitamin B 12; Vitamin B Complex; Vitamin B6; Woman; Work; cancer prevention; cancer risk; case control; cost effective; epidemiologic data; follow-up; improved; insight; interest; men; methyl group; prospective; tool; tumor

One-carbon metabolism is a critical pathway in cancer epigenetics because it directs the methylation of DNA and RNA and is involved in DNA synthesis and repair. There is no good systemic marker of one-carbon metabolism status. Abnormal one-carbon metabolism may lead to genomic (global) hypomethylation in systemic blood DNA, which may predispose the development of neoplasia; if so, genomic methylation status in blood DNA may serve as a good systemic marker of one-carbon metabolism status. Several dietary factors including folate, alcohol, methionine, riboflavin, vitamins B6 and B12, choline, and betaine mediate or facilitate one-carbon metabolism pathway. We currently do not know the optimum balance of these multiple dietary factors to achieve maximum function in the pathway and to minimize cancer risk. Therefore, we propose to evaluate pre-diagnostic genomic methylation of leukocyte DNA in relation to colorectal cancer risk in large prospective studies and expect that individuals with reduced levels of genomic DNA methylation are at increased risk of colorectal cancer. We also propose to elucidate the associations between major plasma components of one-carbon metabolism (total folate, unmetabolized folic acid, 5-methyl-tetrahydrofolate, vitamins B6 and B12, cysteine, homocysteine, and methylene-tetrahydrofolate reductase gene) and genomic DNA methylation, to determine the role of each component in genomic DNA methylation and further validate the biological relevance of genomic methylation assessment in blood DNA. We finally propose to identify dietary predictors of genomic DNA hypomethylation, create a 'dietary methyl score', and examine the score in relation to colorectal adenoma/cancer risks. We hypothesize that the 'dietary methyl score' predicts risks of colorectal adenoma/cancer more strongly than the individual dietary predictors. We will also evaluate 'dietary methyl score' in relation to several molecular and epigenetic subtypes of colorectal cancer including tumors with LINE-1 hypomethylation, CpG island methylator phenotype (CIMP)-high, or microsatellite instability (MSI)- high. This application will take advantage of two large ongoing prospective follow-up studies of women and men with 666/1332 colorectal cancer cases/controls with pre-diagnostic blood samples for genomic methylation status of leukocyte DNA. We also expect to include 6,025 colorectal adenoma and 2,794 colorectal cancer cases to evaluate the relationships with 'dietary methyl score'. With several previously assessed plasma components of one-carbon metabolism and molecular subtypes of colorectal tumor, we are uniquely positioned to address these issues in an extremely time- and cost-effective manner. Our work will elucidate a new insight into how dietary factors and one-carbon metabolism affects the epigenetics of cancer in humans. Genomic methylation in leukocyte DNA can potentially serve as a diagnostic tool or target for cancer prevention because it is potentially modifiable. Dietary methyl score will help produce practical dietary guidelines for cancer prevention.

一碳代谢是癌症表观遗传学中的关键途径，因为它指导DNA甲基化 和RNA，并参与DNA合成和修复。目前还没有一个好的单碳系统标记物 代谢状态异常的一碳代谢可能导致基因组（整体）低甲基化， 系统性血液DNA，这可能使肿瘤的发展;如果是这样，基因组甲基化状态， 血DNA可作为一碳代谢状态的良好系统性标志物。几种饮食因素 包括叶酸、酒精、蛋氨酸、核黄素、维生素B6和B12、胆碱和甜菜碱， 一碳代谢途径我们目前还不知道这些多种膳食的最佳平衡 这些因素可以在通路中实现最大功能并将癌症风险降至最低。因此，我们建议 评估白细胞DNA诊断前基因组甲基化与结直肠癌风险的关系， 前瞻性研究，并预计基因组DNA甲基化水平降低的个体， 结直肠癌的风险增加。我们还建议阐明主要血浆 一碳代谢的组分（总叶酸，未代谢的叶酸，5-甲基-四氢叶酸， 维生素B6和B12、半胱氨酸、高半胱氨酸和亚甲基-四氢叶酸还原酶基因）和基因组 DNA甲基化，确定各组分在基因组DNA甲基化中的作用，并进一步验证 血液DNA中基因组甲基化评估的生物学相关性。最后，我们建议确定 基因组DNA低甲基化的饮食预测因子，创建“饮食甲基评分”，并检查评分 与结直肠腺瘤/癌症风险的关系。我们假设“膳食甲基评分”预测了 结直肠腺瘤/癌症的预测比个体饮食预测更强。我们还将评估“饮食 与包括肿瘤在内的结肠直肠癌的几种分子和表观遗传亚型相关的“甲基评分” LINE-1低甲基化、CpG岛甲基化表型（CIMP）高或微卫星不稳定性（MSI） 高这项应用将利用两项正在进行的大型前瞻性随访研究， 666/1332例结直肠癌病例/对照的男性，具有诊断前血液样本进行基因组 白细胞DNA的甲基化状态。我们还预计包括6，025例结直肠腺瘤和2，794例结直肠腺瘤。 结直肠癌病例，以评估与“膳食甲基评分”的关系。与此前几次 评估血浆成分的一碳代谢和分子亚型的结直肠肿瘤，我们 在以极具时间效益和成本效益的方式解决这些问题方面具有独特的地位。我们的工作将 阐明了饮食因素和一碳代谢如何影响癌症的表观遗传学的新见解， 人类白细胞DNA中的基因组甲基化可以潜在地作为癌症的诊断工具或靶点 预防，因为它是可以改变的。膳食甲基评分将有助于生产实用的膳食 癌症预防指南。