Routine fortification of food with folic acid was implemented in the U.S. in 1996 to reduce the risk of birth defects in newborns. Widespread fortification in combination with supplementation has led to the ingestion of folate at levels that are much higher than ever anticipated. Concern exists that high folic acid intake may contribute to the increase in colorectal cancer (CRC) incidence that was observed subsequent to this mandate. To date, the precise relationship between folate levels and colon tumor formation and progression has not been clearly established. Furthermore, much less attention has been given to the role of folate in patients with ulcerative colitis (UC) who have a strong underlying predisposition to CRC and frequently require folic acid supplementation. The overall goal of this study is to assess the effect of varying concentrations of folic acid on the development of colitis associated neoplasia. Rationale for the proposed experimentation is provided by preliminary data that demonstrate that: 1) plasma folate levels are reduced significantly in nontumor-bearing mice with acute or chronic colitis, as compared to healthy controls, and increase with both progression of disease and the multiplicity of colitis-associated CRC;2) reductions in plasma folate levels by the chemopreventive agent 5-aminosalicylic acid correlate directly with tumor inhibition, providing indirect evidence that high folic acid supplementation may promote colon tumorigenesis;and 3) supplementation of human colon carcinoma cells with folic acid in vitro leads to enhanced NF-kB transcriptional activity. The hypothesis of the proposed studies is that an inverse association exists between dietary concentrations of folic acid and the ability of the intervention to prevent colitis-associated CRC, with higher levels of folic acid enhancing NF-kB signaling and altering DNA methylation.
In Specific Aim 1, the effect of administering varying levels of dietary folic acid, after the establishment of colitis, on colonic inflammation and colon tumor formation will be assessed. The proposed studies will be performed in the clinically relevant azoxymethane/dextran sulfate-sodium mouse model of induced colitis-associated neoplasia;a model that this group established more than a decade ago and has characterized extensively. Total plasma and colonic mucosal folate levels will be measured and correlated with both the degree of tissue inflammation, tumor multiplicity, and proliferative index. In Specifc Aim 2, the impact of varying concentrations of folic acid on the DNA methylation profile of the colonic mucosa (normal and inflamed) will be evaluated using the DREAM assay, a non-biased genome-wide approach. The proposed comprehensive analysis of the effect of folic acid on the development of colitis-associated CRC is anticipated to inform the establishment of cancer preventive guidelines for the use of folic acid supplements in UC patients and provide insight into the potential utility of folate levels as an informative biomarker of cancer susceptibility inthis high-risk population.
The mandated fortification of foods with folic acid, in combination with the use of folate supplements, has dictated a need to examine the effect of high levels of folic acid on the development of colon cancer in patients with ulcerative colitis. Results from the present investigation will contribute to our understanding of the response of the inflamed colon to folic acid exposure and inform the establishment of the first guidelines for the use of folic acid supplements by colitis patients. Implementation of such a policy in a clinical setting could significantly reduce the morbidity and mortality currently associated with the development of colorectal cancer in this high-risk population.