Dietary Methyl Score, Genomic DNA Methylation and Colorectal Cancer

描述（申请人提供）：单碳代谢是癌症表观遗传学中的一个关键途径，因为它指导DNA和RNA的甲基化，并参与DNA的合成和修复。目前还没有很好的单碳代谢状态的系统标志物。异常的单碳代谢可能导致全身血液DNA的基因组（全局）低甲基化，这可能导致肿瘤的发展；如果是这样，血液DNA的基因组甲基化状态可能作为单碳代谢状态的良好系统标记。叶酸、酒精、蛋氨酸、核黄素、维生素B6和B12、胆碱和甜菜碱等饮食因子介导或促进单碳代谢途径。我们目前还不知道这些多种饮食因素之间的最佳平衡，以实现该途径的最大功能，并将癌症风险降至最低。因此，我们建议在大型前瞻性研究中评估诊断前白细胞DNA基因组甲基化与结直肠癌风险的关系，并期望基因组DNA甲基化水平降低的个体患结直肠癌的风险增加。我们还建议阐明单碳代谢的主要血浆成分（总叶酸、未代谢叶酸、5-甲基-四氢叶酸、维生素B6和B12、半胱氨酸、同型半胱氨酸和亚甲基-四氢叶酸还原酶基因）与基因组DNA甲基化之间的关系，以确定每种成分在基因组DNA甲基化中的作用，并进一步验证血液DNA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素，创建“饮食甲基化评分”，并检查该评分与结直肠腺瘤/癌症风险的关系。我们假设“膳食甲基评分”预测结直肠腺瘤/癌症的风险比个体饮食预测因素更强。我们还将评估“膳食甲基评分”与结直肠癌的几种分子和表观遗传亚型的关系，包括LINE-1低甲基化、CpG岛甲基化表型（CIMP）高或微卫星不稳定性（MSI）高的肿瘤。该应用程序将利用两项正在进行的大型前瞻性随访研究，对666/1332例结直肠癌患者/对照组的女性和男性进行研究，并提供诊断前血液样本，以检测白细胞DNA的基因组甲基化状态。我们还希望纳入6025例结直肠腺瘤和2794例结直肠癌病例，以评估与“膳食甲基评分”的关系。有了一些先前评估的单碳代谢和结直肠肿瘤分子亚型的血浆成分，我们具有独特的优势，可以以极具时间和成本效益的方式解决这些问题。我们的工作将阐明饮食因素和单碳代谢如何影响人类癌症的表观遗传学的新见解。白细胞DNA中的基因组甲基化可能作为诊断工具或癌症预防的目标，因为它可能是可修改的。膳食甲基评分将有助于制定预防癌症的实用膳食指南。公共卫生相关性：我们的研究将评估诊断前血液DNA基因组甲基化状态的生物学相关性，作为身体全身甲基化状态的测量和癌症的预测因子。甲基化状态可以潜在地用于癌症的早期检测和癌症预防的目标，因为它是潜在的可修改的。“膳食甲基评分”的建立将呈现影响单碳代谢的多种饮食因素的最佳平衡，以降低癌症风险，并有助于制定实用的癌症预防饮食指南。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Our study will evaluate the biological relevance of pre-diagnostic genomic methylation status of blood DNA as a measure of body's systemic methylation status and a predictor of cancer. The methylation status could be potentially utilized for early detection of cancer and a target for cancer prevention because it is potentially modifiable. Creation of 'dietary methyl score' will present the optimum balance of multiple dietary factors affecting one-carbon metabolism to reduce cancer risk and help produce practical dietary guidelines for cancer prevention.