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RFA CA-03-001: Cooperative Grants for Nutritional Modulation of Genetic Pathways Leading to Cancer

Epidemiology Center for Cancer Prevention
Channing Laboratory
Harvard University
Boston, MA

David J. Hunter, MBBS, SCDPrincipal Investigator:
David J. Hunter, MBBS, SCD

Project Summary

"Folate, 1-Carbon Nutrients, Gene Variants and Colon Cancer"

The overall long-term goal is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. A Cooperative Specialized Center will be established across several institutions (Harvard, Tufts, Dartmouth, and the International Agency for Researcher in Cancer, University of Bergen in Europe, Variagenics and NCI). Data from several studies will be pooled to establish whether higher intake of folic acid reduces the risk of colorectal cancer and whether this reduced risk is greater for people with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and certain genetic variations. Mouse models for colon cancer will be validated. Data and samples from two randomized clinical trials looking at folate supplements will assess certain biomarkers for colon cancer risk.

Project 1

Pooled Analysis of MTHFR Polymorphism, Folate Status, and Colorectal Cancer Risk

Goal

  • To establish the largest available database to determine whether higher intakes of folic acid reduces risk of colorectal cancer, and assess the relationship between biomarkers of folate intake and inherited variation in genes on the one-carbon metabolism pathway and risk of colorectal cancer.

Project 2

Mouse Models for the Study of One-Carbon Nutrients and Carcinogenesis

Goal

  • To further assess and validate mouse models of colon carcinogenesis as systems to examine modification of risk by folate and other contributors to one-carbon metabolism.

Project 3

Interrelationships among Folate, MTHFR, DNA Methylation, Uracil Misincorporation and Colorectal Adenomas

Goal:

  • To assess whether DNA level biomarkers of folate status, and the genomic markers of uracil misincorporation and genomic methylation in peripheral blood lymphocytes and distal colon biopsies represent markers of one-carbon nutrient adequacy and risk of colorectal adenoma reoccurrence using samples and data from two randomized clinical trials of folate supplementation.

The above themes correspond to the three Projects. Two initial Developmental Projects aim to:

  • Develop a transgenic mouse with the null allele for MTHFR and the homologous MTHFR C677T polymorphism, and
  • Explore genetic variation in folate-metabolism genes in relation to plasma folate and homocysteine levels.

Research is supported by two cores

Core A

Administrative and Statistical Core

Core B

Measurement Core

References

Chiuve SE, Giovannucci EL, Hankinson SE, et al. Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine. Am J Clin Nutr 2005 Jul;82(1):155-62. 

Govindarajulu US, Spiegelman D, Miller KL, Kraft P. Quantifying bias due to allele misclassification in case-control studies of haplotypes. Genet Epidemiol 2006 Nov;30(7):590-601.

Koushik A, Kraft P, Fuchs CS, et al. Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. Cancer Epidemiol Biomarkers Prev 2006;15(12):2408-17.

Jang H, Mason JB, Choi SW. Genetic and epigenetic interactions between folate and aging in carcinogenesis. J Nutr 2005 Dec;135(12 Suppl):2967S-2971S.

Mason JB, Choi SW. Effects of alcohol on folate metabolism: implications for carcinogenesis. Alcohol 2005 Apr;35(3):235-41.

Choi SW, Friso S, Keyes MK, Mason JB. Folate supplementation increases genomic DNA methylation in the liver of elder rats. Br J Nutr 2005 Jan;93(1):31-5.

Crott JW, Choi SW, Branda RF, Mason JB. Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats. Mutat Res 2005 Feb 15;570(1):63-70.

Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297(21):2351-9.

Gabriel HE, Liu Z, Crott JW, et al. A comparison of carotenoids, retinoids, and tocopherols in the serum and buccal mucosa of chronic cigarette smokers versus nonsmokers. Cancer Epidemiol Biomarkers Prev 2006;15(5):993-9.

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