Folate, DNA stability and colo-rectal neoplasia

S J Duthie, S Narayanan, L Sharp, J Little, G Basten, H Powers

    Research output: Contribution to journalArticle

    56 Citations (Scopus)

    Abstract

    Lower levels of dietary folate are associated with the development of epithelial cell tumours in man, particularly colo-rectal cancer. In the majority of epidemiological studies blood folate or reported folate intake have been shown to be inversely related to colo-rectal cancer risk. Folate, via its pivotal role in C-1 metabolism, is crucial both for DNA synthesis and repair, and for DNA methylation. This function is compromised when vitamin B-12 is low. Vitamin B-12 deficiency has been shown to increase biomarkers of DNA damage in man but there is no evidence directly linking low vitamin B-12 with cancer. Disturbingly, folate and vitamin B-12 deficiencies are common in the general population, particularly in the underprivileged and the elderly. How folate and/or vitamin B-12 deficiency influence carcinogenesis remains to be established, but it is currently believed that they may act to decrease DNA methylation, resulting in proto-oncogene activation, and/or to induce instability in the DNA molecule via a futile cycle of uracil misincorporation and removal. The relative importance of these two pathways may become clear by determining both DNA stability and cytosine methylation in individuals with different polymorphic variants of key folate-metabolising enzymes. 5,10-Methylenetetrahydrofolate reductase converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and thereby controls whether folate is employed for DNA synthesis or DNA methylation. Colo-rectal cancer risk is decreased in subjects homozygous for a common variant (C677T) of the gene coding for this enzyme, suggesting that DNA synthesis and repair may be 'enhanced' in these individuals. Evidence from animal and human studies is presented here in support of folate acting to maintain genomic stability through both these mechanisms.

    Original languageEnglish
    Pages (from-to)571-578
    Number of pages8
    JournalProceedings of the Nutrition Society
    Volume63
    DOIs
    Publication statusPublished - 2004

    Keywords

    • folate
    • vitamin B-12
    • DNA stability
    • DNA methylation
    • MTHFR
    • colon cancer
    • HAMSTER OVARY CELLS
    • METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM
    • RECOMMENDED DIETARY-ALLOWANCES
    • FOLATE/METHYL-DEFICIENT RATS
    • FOLIC-ACID DEFICIENCY
    • RED-BLOOD-CELLS
    • GENOMIC DNA
    • COMMON MUTATION
    • URACIL MISINCORPORATION
    • PLASMA HOMOCYSTEINE

    Cite this