||5R01CA136950-04 Interpret this number
||Brigham And Women'S Hospital
||Dietary Methyl Score, Genomic DNA Methylation and Colorectal Cancer
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.
Pre-diagnostic leukocyte genomic DNA methylation and the risk of colorectal cancer in women.
Nan H, Giovannucci EL, Wu K, Selhub J, Paul L, Rosner B, Fuchs CS, Cho E
PLoS One, 2013;8(4), p. e59455.
2013 Apr 1.
Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease.
Ogino S, Lochhead P, Chan AT, Nishihara R, Cho E, Wolpin BM, Meyerhardt JA, Meissner A, Schernhammer ES, Fuchs CS, Giovannucci E
Mod Pathol, 2013 Apr;26(4), p. 465-84.
2013 Jan 11.
No association between garlic intake and risk of colorectal cancer.
Meng S, Zhang X, Giovannucci EL, Ma J, Fuchs CS, Cho E
Cancer Epidemiol, 2013 Apr;37(2), p. 152-5.
2012 Dec 21.