The purpose of this review is to outline the principal mechanisms involved
in folate metabolism and how they may relate to the pathogenesis of colorec
tal cancer (CRC). In recent years, mild folate depletion (low normal level)
has been associated with an increased risk of developing certain cancers,
in particular colorectal neoplasia. The epidemiologic and mechanistic evide
nce linking folate deficiency with carcinogenesis is reviewed, with a parti
cular emphasis on colorectal neoplasia. Methylenetetrahydrofolate reductase
(MTHFR) is a critical folate metabolizing enzyme, and a functional polymor
phic variant of this enzyme, the so-called thermolabile variant, caused by
a C677T transition in the MTHFR gene, is common in the general population.
This review critically examines the evidence that suggests that carriers of
this C677T variant may be at increased risk of developing colorectal neopl
asia. Although folate depletion may predispose to the initiation of the neo
plastic process, folate supplementation, on the other hand, might potentiat
e the progression of an already established early neoplastic clone (eg, a c
olorectal adenoma). This could have potential public health implications, g
iven an increasingly widespread policy of folate supplementation of food st
aples.