Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence

It is only recently that folate deficiency has been implicated in the devel opment of cancer. The mechanisms by which folate might protect against canc er are not clear but may relate to its role in DNA methylation and DNA synt hesis. All case-control, cohort and intervention trials reported in English , French, or German, on folate intake or blood levels in relation to the ri sk of colorectal, breast, and cervix cancer were reviewed. Twenty case-cont rol, and 12 nested case-control or cohort studies were identified. The epid emiological studies consistently show an inverse association between intake and/or levels of folate and the frequency of colorectal carcinomas, and le ss 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 mo dulated by alcohol, methionine, and MTHFR polymorphisms. Results from anima l studies suggest that folate supplementation might decrease or increase ca ncer risk depending on dosage and timing. Recent studies also suggest an in verse association between folate intake and breast cancer among women who r egularly consume alcohol. Conversely, epidemiological evidence remains unce rtain for the role of folate in cervical cancer prevention; the results of two intervention trials on rates of cervical intraepithelial neoplasia regr ession or progression were negative. An effect of folate later in carcinoge nesis 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 th at dietary intake or blood levels of folate do not accurately reflect folat e concentrations in the cells of cancer origin. Furthermore, only a few stu dies have taken into account the modulating effect of alcohol, methionine, and MTHFR polymorphisms in their analyses. The observed inverse association s between folate and risk of cancer, on the other hand, may be confounded b y various factors, especially by other potentially protective constituents in fruits and vegetables. Ongoing intervention studies can strengthen evide nce for causality by excluding such confounding, but the optimal dose, dura tion, and stage of carcinogenesis and the appropriate (genetically predispo sed) study group for folate chemoprevention are not yet defined.