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A Methylenetetrahydrofolate Reductase Polymorphism and the Risk of Colorectal Cancer¹

Departments of Epidemiology [J. C., E. B. R., M. J. S., G. A. C., D. S., W. C. W., D. J. H.], Nutrition [E. G., E. B. R., M. J. S., W. C. W.], Environmental Health [K. K.], and Biostatistics [D. S.], Harvard School of Public Health; the Harvard Center for Cancer Prevention [G. A. C., D. J. H.]; and Channing Laboratory, Brigham and Woman's Hospital [J. C., E. G., K. K., E. B. R., M. J. S., G. A. C., W. C. W., D. J. H.], Harvard Medical School, Boston, Massachusetts 02115

We examined the relationship of a common polymorphism (⁶⁶⁷CT) of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of colorectal cancer in a case-control study conducted in the Health Professionals Follow-up Study. MTHFR genotypes were ascertained from blood samples among 144 men previously diagnosed with colorectal cancer and 627 controls. The adjusted odds ratio (OR) for the MTHFR variant homozygous (val/val) genotype was 0.57 [95% confidence interval (CI), 0.30–1.06]. High dietary intake of methionine (OR, 0.27; 95% CI, 0.06–1.20) and low consumption of alcohol (OR, 0.11; 95% CI, 0.01–0.85) were associated with reduced incidence of colorectal cancer. Alcohol intake was a stronger risk factor among men with the val/val genotype (P, trend = 0.01), and consumption of five or more alcoholic drinks per week abolished the reduced risk of colorectal cancer among val/val individuals (P, interaction = 0.02). The inverse association of methionine with colorectal cancer risk was slightly stronger among individuals with the MTHFR val/val genotype. These data suggest that dietary methyl supply is particularly critical among MTHFR val/val individuals. When dietary methyl supply is high, MTHFR val/val individuals may be at reduced risk of colorectal cancer probably because higher levels of 5,10-methylenetetrahydrofolate may prevent imbalances of nucleotide pools during DNA synthesis. In contrast, when 5-methyltetrahydrofolate is depleted by alcohol consumption, val/val individuals may be less able to compensate, leading to potentially oncogenic alterations in DNA methylation.

¹ This study was supported by Research Grants CA55075, CA62984, CA70817, and HL35464 from NIH. J. C. is supported by Training Grant ES07069 and K. K. is supported by Research Grant ES 00002 from the National Institute for Environmental Health Sciences. D. H. is partially supported by American Cancer Society Faculty Research Award FRA-455.

² To whom requests for reprints should be addressed, at Channing Laboratory, 180 Longwood Avenue, Boston, MA 02115.

Received 8/ 6/96. Accepted 9/17/96.

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				J. W. Crott, S. T. Mashiyama, B. N. Ames, and M. Fenech The Effect of Folic Acid Deficiency and MTHFR C677T Polymorphism on Chromosome Damage in Human Lymphocytes in Vitro Cancer Epidemiol. Biomarkers Prev., October 1, 2001; 10(10): 1089 - 1096. [Abstract] [Full Text] [PDF]

				K. Matsuo, R. Suzuki, Y. Morishima, N. Hamajima, C. M. Ulrich, R. Storb, M. M. Schubert, and J. D. Potter Attribution of posttransplantation toxicity to methotrexate regarding genotype of methylenetetrahydrofolate reductase gene (MTHFR) polymorphism needs further clarification Blood, October 1, 2001; 98(7): 2283 - 2283. [Full Text] [PDF]

				R A Sharma, A J Gescher, K J O'Byrne, and W P Steward Familiar drugs may prevent cancer Postgrad. Med. J., August 1, 2001; 77(910): 492 - 497. [Abstract] [Full Text] [PDF]

				J. W. Crott, S. T. Mashiyama, B. N. Ames, and M. F. Fenech Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro Carcinogenesis, July 1, 2001; 22(7): 1019 - 1025. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, Y. Yasui, R. Storb, M. M. Schubert, J. L. Wagner, J. Bigler, K. S. Ariail, C. L. Keener, S. Li, H. Liu, et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism Blood, July 1, 2001; 98(1): 231 - 234. [Abstract] [Full Text] [PDF]

				K. Matsuo, R. Suzuki, N. Hamajima, M. Ogura, Y. Kagami, H. Taji, E. Kondoh, S. Maeda, S. Asakura, S. Kaba, et al. Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma Blood, May 15, 2001; 97(10): 3205 - 3209. [Abstract] [Full Text] [PDF]

				C. Song, D. Xing, W. Tan, Q. Wei, and D. Lin Methylenetetrahydrofolate Reductase Polymorphisms Increase Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population Cancer Res., April 1, 2001; 61(8): 3272 - 3275. [Abstract] [Full Text]

				K. Woodson, J. Mason, S.-W. Choi, T. Hartman, J. Tangrea, J. Virtamo, P. R. Taylor, and D. Albanes Hypomethylation of p53 in Peripheral Blood DNA Is Associated with the Development of Lung Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2001; 10(1): 69 - 74. [Abstract] [Full Text]

				J LITTLE Multivitamins, folate, and colon cancer Gut, January 1, 2001; 48(1): 12 - 13. [Full Text] [PDF]

				C. M. Ulrich, J. Bigler, C. M. Velicer, E. A. Greene, F. M. Farin, and J. D. Potter Searching Expressed Sequence Tag Databases: Discovery and Confirmation of a Common Polymorphism in the Thymidylate Synthase Gene Cancer Epidemiol. Biomarkers Prev., December 1, 2000; 9(12): 1381 - 1385. [Abstract] [Full Text]

				U. Hasbargen, P. Lohse, and C. J. Thaler The number of dichorionic twin pregnancies is reduced by the common MTHFR 677C->T mutation Hum. Reprod., December 1, 2000; 15(12): 2659 - 2662. [Abstract] [Full Text] [PDF]

				M. Ward, H. McNulty, K. Pentieva, J. McPartlin, J. J. Strain, D. G. Weir, and J. M. Scott Fluctuations in Dietary Methionine Intake Do Not Alter Plasma Homocysteine Concentration in Healthy Men J. Nutr., November 1, 2000; 130(11): 2653 - 2657. [Abstract] [Full Text] [PDF]

				B. Tang, Y. N. Li, and W. D. Kruger Defects in Methylthioadenosine Phosphorylase Are Associated with but not Responsible for Methionine-dependent Tumor Cell Growth Cancer Res., October 1, 2000; 60(19): 5543 - 5547. [Abstract] [Full Text]

				W. C. Willett Diet and Cancer Oncologist, October 1, 2000; 5(5): 393 - 404. [Abstract] [Full Text]

				L. L. Stern, J. B. Mason, J. Selhub, and S.-W. Choi Genomic DNA Hypomethylation, a Characteristic of Most Cancers, Is Present in Peripheral Leukocytes of Individuals Who Are Homozygous for the C677T Polymorphism in the Methylenetetrahydrofolate Reductase Gene Cancer Epidemiol. Biomarkers Prev., August 1, 2000; 9(8): 849 - 853. [Abstract] [Full Text]

				J.-H. Yoo, G.-D. Choi, and S.-S. Kang Pathogenicity of Thermolabile Methylenetetrahydrofolate Reductase for Vascular Dementia Arterioscler. Thromb. Vasc. Biol., August 1, 2000; 20(8): 1921 - 1925. [Abstract] [Full Text] [PDF]

				A. J. Levine, K. D. Siegmund, C. M. Ervin, A. Diep, E. R. Lee, H. D. Frankl, and R. W. Haile The Methylenetetrahydrofolate Reductase 677C{->}T Polymorphism and Distal Colorectal Adenoma Risk Cancer Epidemiol. Biomarkers Prev., July 1, 2000; 9(7): 657 - 663. [Abstract] [Full Text]

				C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Lack of Association between the C677T MTHFR Polymorphism and Colorectal Hyperplastic Polyps Cancer Epidemiol. Biomarkers Prev., April 1, 2000; 9(4): 427 - 433. [Abstract] [Full Text]

				F. P. Perera and I.B. Weinstein Molecular epidemiology: recent advances and future directions Carcinogenesis, March 1, 2000; 21(3): 517 - 524. [Abstract] [Full Text] [PDF]

				R S Houlston and I P M Tomlinson Detecting low penetrance genes in cancer: the way ahead J. Med. Genet., March 1, 2000; 37(3): 161 - 167. [Abstract] [Full Text]

				B. N. Ames Cancer prevention and diet: Help from single nucleotide polymorphisms PNAS, October 26, 1999; 96(22): 12216 - 12218. [Full Text] [PDF]

				C. F. Skibola, M. T. Smith, E. Kane, E. Roman, S. Rollinson, R. A. Cartwright, and G. Morgan Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults PNAS, October 26, 1999; 96(22): 12810 - 12815. [Abstract] [Full Text] [PDF]

				S J. James, M. Pogribna, I. P Pogribny, S. Melnyk, R J. Hine, J. B Gibson, P. Yi, D. L Tafoya, D. H Swenson, V. L Wilson, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome Am. J. Clinical Nutrition, October 1, 1999; 70(4): 495 - 501. [Abstract] [Full Text] [PDF]

				J. Ma, M. J. Stampfer, B. Christensen, E. Giovannucci, D. J. Hunter, J. Chen, W. C. Willett, J. Selhub, C. H. Hennekens, R. Gravel, et al. A Polymorphism of the Methionine Synthase Gene: Association with Plasma Folate, Vitamin B12, Homocyst(e)ine, and Colorectal Cancer Risk Cancer Epidemiol. Biomarkers Prev., September 1, 1999; 8(9): 825 - 829. [Abstract] [Full Text]

				W. C Willett Convergence of philosophy and science: the Third International Congress on Vegetarian Nutrition Am. J. Clinical Nutrition, September 1, 1999; 70(3): 434S - 438. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Colorectal Adenomas and the C677T MTHFR Polymorphism: Evidence for Gene-Environment Interaction? Cancer Epidemiol. Biomarkers Prev., August 1, 1999; 8(8): 659 - 668. [Abstract] [Full Text]

				J. D. Potter Colorectal Cancer: Molecules and Populations J Natl Cancer Inst, June 2, 1999; 91(11): 916 - 932. [Abstract] [Full Text] [PDF]

				M. L. Slattery, J. D. Potter, W. Samowitz, D. Schaffer, and M. Leppert Methylenetetrahydrofolate Reductase, Diet, and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., June 1, 1999; 8(6): 513 - 518. [Abstract] [Full Text]