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 C1 metabolism, is crucial both for
DNA synthesis and repair, and for DNA methylation. This function is compromised when
vitamin B12 is low.
Vitamin B12 deficiency has been shown to increase
biomarkers of DNA damage in man but there is no evidence directly linking low
vitamin B12 with
cancer. Disturbingly,
folate and
vitamin B12 deficiencies are common in the general population, particularly in the underprivileged and the elderly. How
folate and/or
vitamin B12 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.