Folic acid and colorectal cancer prevention: molecular mechanisms and epidemiological evidence (Review).

Epidemiological studies suggest that a diet rich in fruits and vegetables protects against colorectal cancer. This effect may result from their high levels of folic acid (pteroylglutamic acid). Folic acid holds a key position in DNA synthesis and mitosis as well as DNA methylation and regulation of gene expression. Folic acid deficiency has been associated with site- and gene specific DNA hypo- and hypermethylation. Furthermore thymidylate synthesis is restricted by folic acid deficiency which causes misincorporation of nucleotides and DNA strand breaks. Much epidemiological evidence supports the hypothesis that insufficient folic acid supply favors the development of colorectal tumors, particularly prospective studies have supported this connection. However, the data from case-control studies are less consistent. Functional polymorphisms in folate-metabolizing genes, especially the methylenetetrahydrofolate reductase (MTHFR) are capable of modifying the risk of colorectal cancer. Observational studies show that individuals with the homozygote genotype for the MTHFR (677C-->T) polymorphism are at higher risk when folic acid supply is low. Currently there are only few human intervention trials which show that folic acid can modify and inhibit the development of colorectal tumors. Additional studies are required in order to determine whether folic acid will be a useful agent in colorectal cancer prevention.