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Methylenetetrahydrofolate Reductase Polymorphism, Dietary Interactions, and Risk of Colorectal Cancer¹

Channing Laboratory [J. M., M. J. S., E. G., D. J. H., C. F., W. C. W., C. H. H.] and Division of Preventive Medicine [C. H. H.], Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; Departments of Nutrition [M. J. S., E. G., W. C. W.] and Epidemiology [M. J. S., D. J. H., W. C. W., C. H. H.], Harvard School of Public Health, Boston, Massachusetts 02115; Department of Human Genetics, Pediatrics, and Biology, McGill University, Montreal Children's Hospital, H3H1P3 Montreal, Quebec, Canada [C. A., R. R.]; and Jean Mayer United States Department of Agriculture Human Nutrition Center on Aging at Tufts University, Boston, Massachusetts 02111 [J. S.]

Folate derivatives are important in experimental colorectal carcinogenesis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate, required for purine and thymidine syntheses, to 5-methyltetrahydrofolate, the primary circulatory form of folate necessary for methionine synthesis. A common mutation (677C T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, and their interaction with risk of colon cancer. We also examined the interaction between genotype and alcohol intake.

We used a nested case-control design within the Physicians' Health Study. Participants were ages 40–84 at baseline when alcohol intake was ascertained and blood samples were drawn. During 12 years of follow-up, we identified 202 colorectal cancer cases and matched them to 326 cancerfree controls by age and smoking status. We genotyped for the MTHFR polymorphism and measured plasma folate levels.

Men with the homozygous mutation (15% in controls) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27–0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal significant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93–3.42) among those whose plasma folate levels indicated deficiency (<3 ng/ml) compared with men with adequate folate levels. Among men with adequate folate levels, we observed a 3-fold decrease in risk (OR, 0.32; 95% CI, 0.15–0.68) among men with the homozygous mutation compared with those with the homozygous normal or heterozygous genotypes. However, the protection due to the mutation was absent in men with folate deficiency. In men with the homozygous normal genotype who drank little or no alcohol as reference, those with the homozygous mutation who drank little or no alcohol had an 8-fold decrease in risk (OR, 0.12; 95% CI, 0.03–0.57), and for moderate drinkers, a 2-fold decrease in risk (OR, 0.42; 95% CI, 0.15–1.20); no decrease in risk was seen in those drinking 1 or more drinks/day.

Our findings provide support for an important role of folate metabolism in colon carcinogenesis. In particular, these results suggest that the 677CT mutation in MTHFR reduces colon cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis, but that low folate intake or high alcohol consumption may negate some of the protective effect.

¹ This work was supported by NIH Research Grants CA 42182 and CA 40360 and the Medical Research Council of Canada.

² To whom requests for reprints should be addressed, at 181 Longwood Avenue, Boston, MA 02115. Phone: (617) 525-2708; Fax: (617) 525-2008.

Received 9/ 6/96. Accepted 1/18/97.

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				Y.-I. Kim Role of Folate in Colon Cancer Development and Progression J. Nutr., November 1, 2003; 133(11): 3731S - 3739. [Abstract] [Full Text] [PDF]

				L. B. Bailey Folate, Methyl-Related Nutrients, Alcohol, and the MTHFR 677C->T Polymorphism Affect Cancer Risk: Intake Recommendations J. Nutr., November 1, 2003; 133(11): 3748S - 3753. [Abstract] [Full Text] [PDF]

				J. Little, L. Sharp, S. Duthie, and S. Narayanan Colon Cancer and Genetic Variation in Folate Metabolism: The Clinical Bottom Line J. Nutr., November 1, 2003; 133(11): 3758S - 3766. [Abstract] [Full Text] [PDF]

				J. Chen, D. J. Hunter, M. J. Stampfer, C. Kyte, W. Chan, J. G. Wetmur, R. Mosig, J. Selhub, and J. Ma Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Modifies the Risk and Survival of Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 958 - 962. [Abstract] [Full Text] [PDF]

				E. Giovannucci, J. Chen, S. A. Smith-Warner, E. B. Rimm, C. S. Fuchs, C. Palomeque, W. C. Willett, and D. J. Hunter Methylenetetrahydrofolate Reductase, Alcohol Dehydrogenase, Diet, and Risk of Colorectal Adenomas Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 970 - 979. [Abstract] [Full Text] [PDF]

				L. Lathrop Stern, B. Shane, P. J. Bagley, M. Nadeau, V. Shih, and J. Selhub Combined Marginal Folate and Riboflavin Status Affect Homocysteine Methylation in Cultured Immortalized Lymphocytes from Persons Homozygous for the MTHFR C677T Mutation J. Nutr., September 1, 2003; 133(9): 2716 - 2720. [Abstract] [Full Text] [PDF]

				M. van Engeland, M. P. Weijenberg, G. M. J. M. Roemen, M. Brink, A. P. de Bruine, R. A. Goldbohm, P. A. van den Brandt, S. B. Baylin, A. F. P. M. de Goeij, and J. G. Herman Effects of Dietary Folate and Alcohol Intake on Promoter Methylation in Sporadic Colorectal Cancer: The Netherlands Cohort Study on Diet and Cancer Cancer Res., June 15, 2003; 63(12): 3133 - 3137. [Abstract] [Full Text] [PDF]

				A. Zijno, C. Andreoli, P. Leopardi, F. Marcon, S. Rossi, S. Caiola, A. Verdina, R. Galati, A. Cafolla, and R. Crebelli Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects Carcinogenesis, June 1, 2003; 24(6): 1097 - 1103. [Abstract] [Full Text] [PDF]

				J. Lokk News and Views on Folate and Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2003; 58(4): M354 - 361. [Abstract] [Full Text] [PDF]

				K. Robien and C. M. Ulrich 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview Am. J. Epidemiol., April 1, 2003; 157(7): 571 - 582. [Abstract] [Full Text] [PDF]

				S.-W. Choi, S. Friso, G. G. Dolnikowski, P. J. Bagley, A. N. Edmondson, D. E. Smith, and J. B. Mason Biochemical and Molecular Aberrations in the Rat Colon Due to Folate Depletion Are Age-Specific J. Nutr., April 1, 2003; 133(4): 1206 - 1212. [Abstract] [Full Text] [PDF]

				B. T. Heijmans, J. M. A. Boer, H. E. D. Suchiman, C. J. Cornelisse, R. G. J. Westendorp, D. Kromhout, E. J. M. Feskens, and P. E. Slagboom A Common Variant of the Methylenetetrahydrofolate Reductase Gene (1p36) Is Associated with an Increased Risk of Cancer Cancer Res., March 15, 2003; 63(6): 1249 - 1253. [Abstract] [Full Text] [PDF]

				F. Orio Jr., S. Palomba, S. Di Biase, A. Colao, L. Tauchmanova, S. Savastano, D. Labella, T. Russo, F. Zullo, and G. Lombardi Homocysteine Levels and C677T Polymorphism of Methylenetetrahydrofolate Reductase in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 673 - 679. [Abstract] [Full Text] [PDF]

				G. C. Rampersaud, G. P.A. Kauwell, and L. B. Bailey Folate: A Key to Optimizing Health and Reducing Disease Risk in the Elderly J. Am. Coll. Nutr., February 1, 2003; 22(1): 1 - 8. [Abstract] [Full Text] [PDF]

				T. Marugame, E. Tsuji, C. Kiyohara, H. Eguchi, T. Oda, K. Shinchi, and S. Kono Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas Int. J. Epidemiol., February 1, 2003; 32(1): 64 - 66. [Abstract] [Full Text] [PDF]

				U. B Fallon Commentary: Colon cancer, folate and genetic status Int. J. Epidemiol., February 1, 2003; 32(1): 67 - 70. [Full Text] [PDF]

				G. Toffoli, R. Gafa, A. Russo, G. Lanza, R. Dolcetti, F. Sartor, M. Libra, A. Viel, and M. Boiocchi Methylenetetrahydrofolate Reductase 677 C->T Polymorphism and Risk of Proximal Colon Cancer in North Italy Clin. Cancer Res., February 1, 2003; 9(2): 743 - 748. [Abstract] [Full Text] [PDF]

				T. Keku, R. Millikan, K. Worley, S. Winkel, A. Eaton, L. Biscocho, C. Martin, and R. Sandler 5,10-Methylenetetrahydrofolate Reductase Codon 677 and 1298 Polymorphisms and Colon Cancer in African Americans and Whites Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1611 - 1621. [Abstract] [Full Text] [PDF]

				M van Rijnsoever, F Grieu, H Elsaleh, D Joseph, and B Iacopetta Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands Gut, December 1, 2002; 51(6): 797 - 802. [Abstract] [Full Text] [PDF]

				M. M. de Jong, I. M. Nolte, G. J. te Meerman, W. T. A. van der Graaf, E. G. E. de Vries, R. H. Sijmons, R. M. W. Hofstra, and J. H. Kleibeuker Low-penetrance Genes and Their Involvement in Colorectal Cancer Susceptibility Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1332 - 1352. [Abstract] [Full Text] [PDF]

				X. Miao, D. Xing, W. Tan, J. Qi, W. Lu, and D. Lin Susceptibility to Gastric Cardia Adenocarcinoma and Genetic Polymorphisms in Methylenetetrahydrofolate Reductase in an At-Risk Chinese Population Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1454 - 1458. [Abstract] [Full Text] [PDF]

				M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]

				E. Giovannucci Epidemiologic Studies of Folate and Colorectal Neoplasia: a Review J. Nutr., August 1, 2002; 132(8): 2350S - 2355. [Abstract] [Full Text] [PDF]

				S. Friso and S.-W. Choi Gene-Nutrient Interactions and DNA Methylation J. Nutr., August 1, 2002; 132(8): 2382S - 2387. [Abstract] [Full Text] [PDF]

				S.-W. Choi and J. B. Mason Folate Status: Effects on Pathways of Colorectal Carcinogenesis J. Nutr., August 1, 2002; 132(8): 2413S - 2418. [Abstract] [Full Text] [PDF]

				S. J. Duthie, S. Narayanan, G. M. Brand, L. Pirie, and G. Grant Impact of Folate Deficiency on DNA Stability J. Nutr., August 1, 2002; 132(8): 2444S - 2449. [Abstract] [Full Text] [PDF]

				P. J. Stover and C. Garza Bringing Individuality to Public Health Recommendations J. Nutr., August 1, 2002; 132(8): 2476S - 2480. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, J. Bigler, R. Bostick, L. Fosdick, and J. D. Potter Thymidylate Synthase Promoter Polymorphism, Interaction with Folate Intake, and Risk of Colorectal Adenomas Cancer Res., June 1, 2002; 62(12): 3361 - 3364. [Abstract] [Full Text] [PDF]

				A. Melse-Boonstra, A. de Bree, P. Verhoef, A. L. Bjorke-Monsen, and W.M. M. Verschuren Dietary Monoglutamate and Polyglutamate Folate Are Associated with Plasma Folate Concentrations in Dutch Men and Women Aged 20-65 Years J. Nutr., June 1, 2002; 132(6): 1307 - 1312. [Abstract] [Full Text] [PDF]

				B Shannon, S Gnanasampanthan, J Beilby, and B Iacopetta A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability Gut, April 1, 2002; 50(4): 520 - 524. [Abstract] [Full Text] [PDF]