Fuchs et al. found that a higher level of total folate intake had only a minimal protective effect on colon cancer risk among women without a family history of colorectal cancer in first-degree relatives but was associated with a substantial reduction in risk among women with a family history of the disease. Consistent with this, Slattery et al. observed a fivefold increased risk of colon cancer for a low-methyl diet among women who reported a first-degree family history of colorectal cancer, compared to a 1.5-fold risk among those without a family history.

Many of the genes involved in the absorption, metabolism, and transport of folate contain common genetic variants. Several studies have investigated two common variants of the gene encoding 5,10-methylenete-trahydrofolate reductase (MTHFR), C677T and A1298C, in relation to colorectal neoplasia. In most studies, these variants are associated with moderately reduced colorectal cancer risk. Findings from six studies of C677T and adenomatous polyps are inconsistent.

In studies in which joint effects of MTHFR genotype and diet have been investigated, those homozygous for the C677T variant who had higher folate levels (or a high-methyl diet) had the lowest cancer risk.

As yet, too few investigations on other polymorphisms in the folate pathway - such as variants of the gene coding for methionine synthase (MTR) methionine synthase reductase (MTRR), cystathione b-synthase (CBS), or thymidylate synthase (TS)  - have been carried out to be conclusive. While the metabolism of any exposure is likely to depend on the balance between the relative activities of all the enzymes active within the metabolic pathway, to date joint effects of folate-pathway genes have only been little investigated.

Rebecca A. Barnetson and Malcolm G. Dunlop
Colon Cancer Genetics Group, University of Edinburgh, School of Molecular and Clinical Medicine and MRC Human Genetics Unit, Western General Hospital, Edinburgh, U.K.

References