Division of cells with unrepaired or misrepaired DNA
damage leads to mutations. If these relate to critical
genes, such as proto-oncogenes or tumour suppressor
genes, cancer may result. Folate is essential for
DNA synthesis and repair through its role in purine
and pyrimidine synthesis. Its role in the synthesis of
S-adenosylmethionine (SAM) is also relevant to cancer.
SAM donates its methyl group to DNA, among
other acceptors, and a defi ciency of folate can lead to
hypomethylation of DNA. As DNA methylation is a
mechanism for silencing transcription (Ng & Bird,
1999), hypomethylation of DNA has the potential
to alter the normal control of gene expression. Hypomethylation
also alters chromatin conformation,
thereby allowing access of DNA-damaging agents and
endonucleases, which destabilize the DNA and make
it more susceptible to strand breaks (Kim et al., 1997).
Imbalanced DNA methylation is a common occurrence
in carcinogenesis (Laird & Jaenisch, 1994).
Low cytosolic levels of 5,10-methylene-THF associated
with folate defi ciency result in decreased synthesis
of deoxythymidine monophosphate (dTMP) and
the accumulation of deoxyuridine monophosphate
(dUMP). This leads to DNA polymerase-mediated
incorporation of dUMP into the DNA molecule in
place of dTMP. Normal DNA repair processes remove
the misincorporated dUMP, forming transient singlestrand
breaks (nicks) that could result in a doublestrand
break if two opposing nicks are formed. Kim
et al. (1997) showed that, in rats, dietary folate depletion
is capable of producing DNA strand breaks and
hypomethylation within a highly conserved region of
the p53 tumour suppressor gene. The p53 gene was
chosen for study because alterations in it have been
implicated in >50% of human cancers. On a genomewide
basis such alterations either did not occur or
were delayed, indicating some selectivity for the exons
examined within the p53 gene.
In epidemiological studies, dietary folate deficiency
is associated with an increased risk of several specific malignancies, notably cancer of the cervix, lung,
colorectum and brain (Glynn & Albanes, 1994). The
presence of micronucleated erythrocytes in marginal
folate defi ciency is indicative of chromosomal damage
(Everson et al., 1988). Both high DNA dUMP
levels and elevated erythrocyte/reticulocyte micronucleus
frequency are reversed by folate administration
(Blount et al., 1997). Duthie & Hawdon (1998)
showed that a dietary intake of folate adequate for the
prevention of clinical defi ciency may not be suffi cient
to maintain DNA stability.
In a study of American male physicians, Ma et al.
(1997) showed that the C677T polymorphism in the
MTHFR gene reduces the risk of colorectal cancer.
Subjects with the homozygous mutation (15% in controls)
had half the risk of colorectal cancer (odds ratio
0.49; 95% confi dence interval 0.27 to 0.87) compared
with the homozygous normal or heterozygous genotypes.
The protection due to the polymorphism was
absent in subjects with folate defi ciency and reduced
in those with high alcohol consumption. It can be
reasoned that, provided folate status is adequate, the
reduced activity of the thermolabile MTHFR enzyme
variant would lead to an increased level of intracellular
5,10-methylene-THF and this would reduce the
likelihood of dUMP misincorporation into DNA.