Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies

A growing body of evidence implicates alcohol intake as a risk factor for colorectal cancer. Until recently, most of the data were based on epidemiologic data that examined alcohol intake in relation to risk of colorectal neoplasia, but the evidence has now been broadened by recent molecular studies on mechanisms. In particular, a number of observations strongly support a role for alcohol acting through disruptions in one-carbon metabolism. Excessive alcohol intake is a fairly consistent risk factor for colorectal neoplasia in most studies, and studies show much higher risks of colorectal neoplasia in those with high alcohol and low folate than with high alcohol or low folate individually. Interactions between high alcohol-low folate and the MTHFR677TT genotype with risk of colorectal neoplasia suggest that alcohol is acting through its effects on one-carbon metabolism because the combination of high alcohol-low folate and the MTHFR677TT genotype are related to markedly elevated serum levels of homocysteine and to DNA hypomethylation. In addition, in Japanese studies, consumers of alcohol possessing the ALDH2*2 allele, who have very elevated levels of acetaldehyde, are at high risk for colorectal cancer. The relatively high prevalence of the ALDH2*2 allele may thus account for the stronger association between alcohol and colorectal neoplasia that is frequently observed in studies in Japanese populations. Further research integrating studies with more detailed data on alcohol intake levels and patterns, folate and other related nutrient status, and relevant genotypes may help clarify unresolved questions regarding the health consequences of moderate to high alcohol drinking.