© 1995 by Oxford University Press
Journal of the National Cancer Institute, Vol. 87, No. 4, 265-273,
February 15, 1995
© 1995 Oxford University Press
Alcohol, Low-Methionine-Low-Folate Diets, and Risk of Colon Cancer in Men
1Charming Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital Boston, Mass
2Department of Epidemiology and Department of Nutrition, Harvard School of Public Health Boston
3Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital; and Department of Epidemiology and Department of Nutrition, Harvard School of Public Health
4Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital; and Department of Epidemiology, Harvard School of Public Health
Correspondence to: Edward Giovannucci, M.D., Channing Laboratory, 180 Longwood Ave., Boston, MA 02115.
Background: Methylation of DNA, which may have a role in the regulation of gene expression, depends on dietary folate and methionine. Because aberrant DNA methylation may contribute to the initiation or progression of colon cancer, we hypothesized that deficient intakes of folate or methionine and high consumption of alcohol, an antagonist of methyl-group metabolism, increase risk of colon neoplasia. Previously, a high-alcohol and low-methionine-low-folate (methyl-deficient) diet was shown to be related to a higher risk of colon adenomas, precursors of cancer. Purpose: Our goal was to determine if ingestion of a high-alcohol, methyl-deficient diet is related directly to risk of colon cancer. Methods: We assessed dietary intake for a 1-year period for a cohort of 47 931 U.S. male health professionals, 40.75 years old and free of diagnosed cancer in 1986. We assessed diet by using a validated, semiquantitative food-frequency questionnaire. During 6 years of follow-up, we documented 205 new cases of colon cancer in this cohort. Results: Current alcohol intake was directly related to risk of colon cancer (multivariate relative risk [RR] = 2.07; 95% confidence interval [CI] = 1.29–3.32, for >2 drinks versus <0.25 drink daily; P trend = .005), and past drinkers were also at higher risk (RR = 1.95; 95% CI = 1.22–3.10). Individually, folate and methionine intakes were weakly inversely associated with risk of colon cancer. An adverse effect of a high-alcohol, low-methyl diet was not observed among regular users of aspirin, who have previously been shown to be at lower risk for colon cancer. Combinations of high alcohol and low methionine and folate intakes yielded striking associations for total colon cancer (RR = 3.30 [95% CI = 1.58–6.88] comparing high-methyl diets with low-methyl diets among nonusers of aspirin) and for cancers of the distal colon (RR = 7.44; 95% CI = 1.72–32.1). Among men with high intakes of folate or methionine, alcohol levels of >2 drinks daily were not associated with risk of colon cancer. The increased risk of colon cancer associated with alcohol and methyl-deficient diets was not confounded by smoking; intakes of fat, red meat, and fiber; level of physical activity; multivitamin or aspirin use; and body mass index. Conclusions: These findings support the hypothesis that sub-stantial consumption of alcohol, when combined with inadequate intakes of folate and methionine, may increase risk of colon cancer and confirm similar findings in adenomas.Implications: These data provide further support of recommendations to avoid excess alcohol consumption and to increase dietary folate to lower the risk of colon cancer. [J Natl Cancer Inst 87: 265-273, 1995]
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S. A. Ross and L. Poirier Proceedings of the Trans-HHS Workshop: Diet, DNA Methylation Processes and Health J. Nutr., August 1, 2002; 132(8): 2329S - 2332. [Full Text] [PDF]
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E. Giovannucci Epidemiologic Studies of Folate and Colorectal Neoplasia: a Review J. Nutr., August 1, 2002; 132(8): 2350S - 2355. [Abstract] [Full Text] [PDF]
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J. D. Potter Methyl Supply, Methyl Metabolizing Enzymes and Colorectal Neoplasia J. Nutr., August 1, 2002; 132(8): 2410S - 2412. [Abstract] [Full Text] [PDF]
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K. M. Fairfield and R. H. Fletcher Vitamins for Chronic Disease Prevention in Adults: Scientific Review JAMA, June 19, 2002; 287(23): 3116 - 3126. [Abstract] [Full Text] [PDF]
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C. S. Fuchs, W. C. Willett, G. A. Colditz, D. J. Hunter, M. J. Stampfer, F. E. Speizer, and E. L. Giovannucci The Influence of Folate and Multivitamin Use on the Familial Risk of Colon Cancer in Women Cancer Epidemiol. Biomarkers Prev., March 1, 2002; 11(3): 227 - 234. [Abstract] [Full Text] [PDF]
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M. J. Thun, S. J. Henley, and C. Patrono Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues J Natl Cancer Inst, February 20, 2002; 94(4): 252 - 266. [Abstract] [Full Text] [PDF]
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S. Sibani, S. Melnyk, I. P. Pogribny, W. Wang, F. Hiou-Tim, L. Deng, J. Trasler, S.J. James, and R. Rozen Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice Carcinogenesis, January 1, 2002; 23(1): 61 - 65. [Abstract] [Full Text] [PDF]
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 W. C. Willett and M. J. Stampfer What Vitamins Should I Be Taking, Doctor? N. Engl. J. Med., December 20, 2001; 345(25): 1819 - 1824. [Full Text] [PDF]
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M. J. Shrubsole, F. Jin, Q. Dai, X.-O. Shu, J. D. Potter, J. R. Hebert, Y.-T. Gao, and W. Zheng Dietary Folate Intake and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study Cancer Res., October 1, 2001; 61(19): 7136 - 7141. [Abstract] [Full Text] [PDF]
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U A Simanowski, N Homann, M Knuhl, L Arce, R Waldherr, C Conradt, F X Bosch, and H K Seitz Increased rectal cell proliferation following alcohol abuse Gut, September 1, 2001; 49(3): 418 - 422. [Abstract] [Full Text] [PDF]
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L. A. Poirier, C. K. Wise, R. R. Delongchamp, and R. Sinha Blood Determinations of S-Adenosylmethionine, S-Adenosylhomocysteine, and Homocysteine: Correlations with Diet Cancer Epidemiol. Biomarkers Prev., June 1, 2001; 10(6): 649 - 655. [Abstract] [Full Text] [PDF]
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A. Schatzkin and A. Flood Response J Natl Cancer Inst, May 16, 2001; 93(10): 791a - 792a. [Full Text] [PDF]
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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]
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R. Z. Stolzenberg-Solomon, P. Pietinen, M. J. Barrett, P. R. Taylor, J. Virtamo, and D. Albanes Dietary and Other Methyl-Group Availability Factors and Pancreatic Cancer Risk in a Cohort of Male Smokers Am. J. Epidemiol., April 1, 2001; 153(7): 680 - 687. [Abstract] [Full Text] [PDF]
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T. J. Hartman, K. Woodson, R. Stolzenberg-Solomon, J. Virtamo, J. Selhub, M. J. Barrett, and D. Albanes Association of the B-Vitamins Pyridoxal 5'-Phosphate (B6), B12, and Folate with Lung Cancer Risk in Older Men Am. J. Epidemiol., April 1, 2001; 153(7): 688 - 693. [Abstract] [Full Text] [PDF]
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C. H Halsted Lifestyle effects on homocysteine and an alcohol paradox Am. J. Clinical Nutrition, March 1, 2001; 73(3): 501 - 502. [Full Text] [PDF]
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K. M Koehler, R. N Baumgartner, P. J Garry, R. H Allen, S. P Stabler, and E. B Rimm Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use Am. J. Clinical Nutrition, March 1, 2001; 73(3): 628 - 637. [Abstract] [Full Text] [PDF]
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W. C. Willett Diet and Cancer: One View at the Start of the Millennium Cancer Epidemiol. Biomarkers Prev., January 1, 2001; 10(1): 3 - 8. [Abstract] [Full Text]
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J LITTLE Multivitamins, folate, and colon cancer Gut, January 1, 2001; 48(1): 12 - 13. [Full Text] [PDF]
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M. J. Weyant, A. M. Carothers, A. J. Dannenberg, and M. M. Bertagnolli (+)-Catechin Inhibits Intestinal Tumor Formation and Suppresses Focal Adhesion Kinase Activation in the Min/+ Mouse Cancer Res., January 1, 2001; 61(1): 118 - 125. [Abstract] [Full Text]
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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]
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K. B. Michels, Edward Giovannucci, K. J. Joshipura, B. A. Rosner, M. J. Stampfer, C. S. Fuchs, G. A. Colditz, F. E. Speizer, and W. C. Willett Prospective Study of Fruit and Vegetable Consumption and Incidence of Colon and Rectal Cancers J Natl Cancer Inst, November 1, 2000; 92(21): 1740 - 1752. [Abstract] [Full Text] [PDF]
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T. K. Murphy, E. E. Calle, C. Rodriguez, H. S. Kahn, and M. J. Thun Body Mass Index and Colon Cancer Mortality in a Large Prospective Study Am. J. Epidemiol., November 1, 2000; 152(9): 847 - 854. [Abstract] [Full Text] [PDF]
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J. Song, A. Medline, J. B. Mason, S. Gallinger, and Y.-I. Kim Effects of Dietary Folate on Intestinal Tumorigenesis in the ApcMin Mouse Cancer Res., October 1, 2000; 60(19): 5434 - 5440. [Abstract] [Full Text]
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 W. C. Willett Diet and Cancer Oncologist, October 1, 2000; 5(5): 393 - 404. [Abstract] [Full Text]
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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]
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W. W. and C. M. Higuchi Dietary Soy Protein Is Associated with Reduced Intestinal Mucosal Polyamine Concentration in Male Wistar Rats J. Nutr., July 1, 2000; 130(7): 1815 - 1820. [Abstract] [Full Text]
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P. A. Janne and R. J. Mayer Chemoprevention of Colorectal Cancer N. Engl. J. Med., June 29, 2000; 342(26): 1960 - 1968. [Full Text] [PDF]
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J. Song, K.-J. Sohn, A. Medline, C. Ash, S. Gallinger, and Y.-I. Kim Chemopreventive Effects of Dietary Folate on Intestinal Polyps in Apc+/- Msh2-/- Mice Cancer Res., June 1, 2000; 60(12): 3191 - 3199. [Abstract] [Full Text]
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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]
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T. E. Rohan, M. G. Jain, G. R. Howe, and A. B. Miller Dietary Folate Consumption and Breast Cancer Risk J Natl Cancer Inst, February 2, 2000; 92(3): 266 - 269. [Full Text] [PDF]
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