The role of B-vitamins - gene interactions in colorectal carcinogenesis: A molecular epidemiological approach

Folate deficiency can affect DNA methylation and DNA synthesis. Both factors may be operative in colorectal carcinogenesis. Many enzymes, like methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MTR), and serine hydroxymethyltransferase (SHMT), are needed for conversions in folate metabolism. Flavin adenine dinucleotide, a metabolite of vitamin B2, is a cofactor for MTHFR; vitamin B6 is a cofactor for SHMT; and vitamin B12 is a cofactor for MTR. Polymorphisms exist in most of the genes encoding the enzymes that play a role in folate metabolism. Therefore, genetic variation might influence DNA methylation and synthesis processes and thus colorectal carcinogenesis. This thesis describes studies that have been conducted to clarify the role of folate, related B-vitamins, and genetic variation in colorectal carcinogenesis.

In a meta-analysis of human observational studies on the association between folate intake and risk of colorectal adenomas, includingdata from 4 cohort studies and 10 case-control studies, pooled relative risks (95% confidence interval (CI)) for highestvs.lowest exposure category of 0.85 (0.71;1.01) for dietary folate intake and 0.75 (0.61;0.93) for total folate intake were found.

In a Dutch case-control study, including data of colorectal adenoma cases (n=768) and endoscopy controls with no history colorectal polyps (n=709), a slightly positive association between folate and colorectal adenoma risk (odds ratio (OR) highest vs. lowest tertile 1.32, 95% CI 1.01;1.73), and an inverse association between vitamin B2 intake and colorectal adenoma risk (OR highestvs.lowest tertile 0.51, 95% CI 0.36;0.73) was found, especially among those withMTHFR 677 TTgenotype. A null association was found for vitamin B6 and vitamin B12. Furthermore, the combined intake of B-vitamins might be important: the positive association between folate intake and colorectal adenomas seemed to be more pronounced among those with low vitamin B2 intakes. The polymorphisms in the folate metabolism studied (MTHFR, TSandSHMT1) did not seem to influence colorectal adenoma risk when dietary factors were not taken into account. Furthermore, relatively high folate intake (>212μg/day) was mildly inversely associated with promoter methylation of six selected tumor suppressor and DNA repair genes in adenoma tissue as compared with low folate intake (<183μg/day), with statisticallynon-significant ORs ranging from 0.54 to 0.86. This effect was mainly restricted to those carrying theMTHFR 677 TTgenotype.

In a randomized, controlled intervention study including 86 subjects with a history of colorectal adenomas, a high dosage of synthetic folic acid (5 mg/day) and vitamin B12 (1.25 mg/day) for six months seemed to increase uracil incorporation (Δ_intervention-Δ_placebo0.45, 95% CI -0.19;1.09) and promoter methylation of six selected tumor suppressor and DNA repair genes(OR _{upmethylation} 1.67, 95% CI 0.95;2.95), both biomarkers measured inDNA from rectal mucosa biopsies. Again, the effect seemed more pronounced in those with theMTHFR 677 TTgenotype.

The results of these relatively small studies suggest that a potential adverse effect of folic acid should be considered, especially when administered after colorectal neoplastic lesions have been established. However, these results need to be confirmed by larger studies among other populations with similar relatively low intakes of vitamin B2, in which theMTHFR C677Tgenotype or other polymorphisms in folate metabolism should be taken into account.