Folate and colon cancer: Epi, genetics, and epigenetics.

CS06-02

Folate is a B-vitamin that is essential for one-carbon transfer reactions. These include methylation reactions, including the methylation of DNA or other substrates, and also the provision of thymidine and purines, which are needed for DNA synthesis and repair. A role of folate in carcinogenesis is supported by epidemiologic observations of inverse associations with the nutrient itself, by animal experimental studies, and by molecular epidemiologic studies that show associations between folate-related polymorphisms and cancer risk, particularly for colorectal and hematopoietic malignancies [1, 2]. The biologic mechanisms for the folate-cancer relationship are not yet well defined [3]. The link of folate deficiency to reduced provision of nucleotides with subsequent DNA damage is well established. However, the relationship between folate status and epigenetic changes is less obvious, in parts because DNA methylation disturbances that occur during carcinogenic processes involve both global DNA methylation, largely at repeat or satellite regions of DNA, as well as promoter-specific DNA hypermethylation, which is associated with gene silencing. Initial observations suggest that folate status is important for influencing the degree of global DNA methylation, but that epigenetic gene silencing may be caused by other mechanisms, independent of folate status. The timing of folate administration during the carcinogenic process can result in differential effects; higher folate status is expected to protect against mutations, thus reducing the initial progression towards pre-malignant lesions. At the same time, higher folate status may also enhance the growth of a tumor, such as a colorectal polyp, because folate is needed for nucleotide synthesis [4-6]. The latter relationship raises important questions regarding the use of supplements among cancer patients. New insights into the complex nature of folate in carcinogenesis can be obtained by mathematical modeling. Our group has created a mathematical model based on the biochemical properties of folate-mediated one-carbon metabolism. The model can be used to simulate gene-gene or gene-environment interactions, as well as experimental conditions [7]. Predictions from this "in silico metabolomics" approach can help target or inform epidemiologic and experimental research and may also provide an avenue for pathway-based epidemiologic data analyses [8]. Similarly, modeling of the bi-modal effects of folate in colon carcinogenesis and the predicted effect on population cancer rates is underway. Resolving the puzzle of folate and cancer calls for an interdisciplinary approach. In light of the high use of folic-acid containing supplements in the population and fortification of foods, answers are needed. References 1. Giovannucci, E, Epidemiologic studies of folate and colorectal neoplasia: a review. Journal of Nutrition. 2002; 132(8 Suppl): 2350S-2355S. 2. Ulrich, CM, Nutrigenetics in cancer research--folate metabolism and colorectal cancer. J Nutr 2005; 135(11): 2698-702. 3. Choi, SW and JB Mason, Folate and carcinogenesis: an integrated scheme. Journal of Nutrition 2000; 130(2): 129-32. 4. Ulrich, CM and JD Potter, Folate supplementation -- too much of a good thing? Cancer Epidemiology, Biomarkers & Prevention 2006; 15(2): 189-93. 5. Ulrich, CM, K Robien, and HL McLeod, Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nat Rev Cancer 2003; 3(12): 912-20. 6. Kim, YI, Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 2004; 80(5): 1123-8. 7. Reed, MC, HF Nijhout, ML Neuhouser, JF Gregory, 3rd, B Shane, SJ James, A Boynton, and CM Ulrich, A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. J Nutr 2006; 136(10): 2653-61. 8. Ulrich, CM, HF Nijhout, and MC Reed, Mathematical modeling: epidemiology meets systems biology. Cancer Epidemiology, Biomarkers & Prevention 2006; 15(5): 827-9.