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.