It is only recently that
folate deficiency has been implicated in the development of
cancer. The mechanisms by which
folate might protect against
cancer are not clear but may relate to its role in DNA methylation and
DNA synthesis. All case-control, cohort and intervention trials reported in English, French, or German, on
folate intake or blood levels in relation to the risk of colorectal, breast, and
cervix cancer were reviewed. Twenty case-control, and 12 nested case-control or cohort studies were identified. The epidemiological studies consistently show an inverse association between intake and/or levels of
folate and the frequency of
colorectal carcinomas, and less clearly of
adenomas. Long-term use of supplements of
folate seems to be of greater benefit than dietary intake. The effect of
folate seems to be modulated by alcohol,
methionine, and MTHFR polymorphisms. Results from animal studies suggest that
folate supplementation might decrease or increase
cancer risk depending on dosage and timing. Recent studies also suggest an inverse association between
folate intake and
breast cancer among women who regularly consume alcohol. Conversely, epidemiological evidence remains uncertain for the role of
folate in
cervical cancer prevention; the results of two intervention trials on rates of
cervical intraepithelial neoplasia regression or progression were negative. An effect of
folate later in
carcinogenesis is not supported by the few (nested) case-control studies on invasive
cervical cancer. Some of the conflicting results may be due to the fact that dietary intake or blood levels of
folate do not accurately reflect
folate concentrations in the cells of
cancer origin. Furthermore, only a few studies have taken into account the modulating effect of alcohol,
methionine, and MTHFR polymorphisms in their analyses. The observed inverse associations between
folate and risk of
cancer, on the other hand, may be confounded by various factors, especially by other potentially protective constituents in fruits and vegetables. Ongoing intervention studies can strengthen evidence for causality by excluding such confounding, but the optimal dose, duration, and stage of
carcinogenesis and the appropriate (genetically predisposed) study group for
folate chemoprevention are not yet defined.