Diet, nutrition and cancer

Part VI

Interaction among folate, riboflavin, genotype, and cancer, with reference to colorectal and cervical cancer

Folate, riboflavin, genotype, and colorectal cancer

Evidence from human studies for a role for folate in determining cancer risk is equivocal. Much of the work in this area has concerned colorectal cancer, for which there is evidence from epidemiological studies for a protective role for folate. A number of case-control studies have demonstrated an inverse association between folate intake and risk of colorectal cancer, with an average reduction of about 30 percent for the highest versus the lowest folate intakes. Interestingly, alcohol intake may mitigate protective effects of folate. Results of studies examining association between biochemical measures of folate status and risk of colorectal adenoma or cancer are inconsistent. Perhaps of particular relevance is the observation that folate concentration in the healthy mucosa of patients with colorectal adenoma was lower than in control subjects even though circulating folate concentrations did not differ between these two groups. However, others reported no difference in folate concentration in colonocytes from normal tissue between patients with colorectal adenoma and healthy controls. It would be helpful to establish whether folate concentrations in colonic mucosa are sensitive to changes in folate intakes.

Very few folate intervention trials have been carried out, and those that have been reported have been small studies focusing on patient groups with increased risk of colorectal cancer. Furthermore, outcomes of interest have in almost all cases been intermediate disease endpoints, such as DNA methylation, mucosa cell proliferation, or DNA strand breakage. Results are inconsistent. A reduction in rectal cell proliferation in response to 3 mo. of folic acid supplementation in patients with ulcerative colitis, whereas a study in Greece failed to show a significant effect of folic acid supplementation for 12 mo. on adenoma recurrence. On the other hand, showed an increase in rectal mucosa DNA methylation after high-dose folic acid treatment for 6 mo. Clearly, additional folate intervention trials in humans are needed, and the results of 3 large-scale intervention trials in the United States are eagerly awaited. However, in view of the complexity and expense of such trials, there remains an interest in the development of biomarkers of cancer risk that are both responsive to exposure to the nutrient of interest while also reflecting cancer risk.

In light of those studies suggesting a modulating effect of MTHFR C677T genotype in determining functional folate status, it is reasonable to consider the importance of this polymorphism in determining cancer risk. In the 2004 review of this subject it showed that the majority of studies suggest a protective role for this polymorphism.

A further complicating factor that should be factored into new studies is the possible role of riboflavin. Although FAD acts as a cofactor for MTHFR and riboflavin intake influences functional folate status, few studies have examined the possible contribution that riboflavin might make to protection against cancer. Of interest therefore are results from 2 case-control studies that suggest a protective effect of an interaction between riboflavin and the TT variant of MTHFR C677T to reduce a risk of colorectal cancer. These observations are supported by data showing an interaction between riboflavin and folate and this polymorphism in the MTHFR gene to determine genomic stability in cultured human lymphocytes.

Further suggestion of an interaction among folate, MTHFR C677T, and riboflavin that may be relevant to cancer risk comes from a randomized, placebo-controlled intervention trial we recently conducted in volunteers with normal mucosa and those with adenomatous polyps. Subjects in both groups were randomly assigned to a 50-d intervention of placebo, 400ug folic acid (low folate), 400ug folic acid with 5mg riboflavin (low folate plus riboflavin), or 1.2mg folic acid (high folate). Subjects were stratified according to genotype for the C677T polymorphism. Of interest in the present context was the fact that the riboflavin supplement enhanced the systemic response to low-dose folic acid in polyp patients with at least 1T allele, which may reflect a mitigating action of additional flavins on the lower activity of the thermolabile vibrant. Furthermore, the high-folate supplement elicited a modest but significant reduction in riboflavin status compared with the low-folate supplement, an effect of folate that we reported before and that deserves further investigation.