Association of Oral Cancers With Alcohol Consumption: Exploring Mechanisms
Authors: E. L. Harris
Journal: JNCI Journal of the National Cancer Institute (1997)

Cancer results from a series of genetic and epigenetic changes that can occur via multiple pathways. Genetic changes can be inherited, but most individuals do not inherit these changes. Instead, they inherit genes that make their cells more or less susceptible to acquiring and maintaining such changes through mechanisms such as carcinogen metabolism (activation and detoxification), DNA repair proficiency, or immune function; nongenetic factors, such as nutritional components, may also affect this susceptibility. It is within this milieu that environmental agents cause cancer. In this issue of the Journal, two groups of investigators (1,2) examine underlying mechanisms and cofactors of an environmental cause of oral cancers—alcohol. Oral cavity and pharyngeal cancers are strongly associated with tobacco and alcohol use (3,4). The explanation for increased cancer risk associated with increasing alcohol consumption is not complete (4), but it is believed to be due, at least in part, to the carcinogenic effect of the first metabolite of ethanol, acetaldehyde. Alcohol dehydrogenases metabolize ethanol to acetaldehyde, which is then metabolized to acetate by aldehyde dehydrogenases. The focus of these investigators (1,2) is on factors that affect the metabolism of ethanol to acetaldehyde, a carcinogen. Harty et al. (1) assessed the association between oral cancers and variation in the gene coding for alcohol dehydrogenase type 3 (ADH3) among humans; using a rat model, Homann et al. (2) assessed the effects of acetaldehyde on the upper gastrointestinal tract mucosa to provide support for the impact of bacterial metabolism of alcohol on oral cancer risk. Harty et al. (1) studied the association between polymorphisms in ADH3, alcohol consumption, and cancers of the oral cavity and pharynx in Puerto Rico. There are two common alleles for ADH3, designated 1 and 2, which vary in frequency across racial and ethnic groups. The ADH3 genotype affects the metabolism of alcohol to acetaldehyde. Individuals homozygous for ADH3 allele 1 (ADH3 ) metabolize alcohol to acetaldehyde faster than individuals who carry at least one ADH3 allele 2 (ADH3 1–2 or ADH3 ). Thus, individuals who drink alcohol and who are homozygous for ADH3 allele 1 may be at increased risk of developing oral cancers. The findings of Harty et al. suggest that this is the case. Alcohol consumption of 15 or more drinks per week increased oral cancer risk; ADH3 genotype had no overall effect on oral cancer risk. However, when stratified on alcohol consumption level, the effect of ADH3 genotype is clear: It has no effect on cancer risk for individuals who are nondrinkers or who consume fewer than 57 drinks a week; however, heavy drinkers who are ADH3 1–1 have a greatly increased risk of oral cancers when compared with nondrinkers and with heavy drinkers who have other ADH3 genotypes. This study illustrates two points. First, the effect of genes (or any factor) on risk may be inadequately assessed if one does not consider cofactors and their interactions that are also important in that pathway. If Harty et al. had not considered gene– environment interaction, the effect of ADH3 on risk would have been underestimated or completely missed. Second, for most conditions, there is more than one way for an exposure to have an impact on risk. In this study, variation in oral cancer risk among heavy drinkers is partly explained by ADH3 genotype. Other factors must explain the variation in risk among lighter drinkers and nondrinkers, which brings us to the article by Homann et al. (2) in this issue of the Journal. Homann et al. (2) examined the cellular effects of acetaldehyde on squamous epithelia of the upper gastrointestinal tract of rats; they hypothesized that part of the effect of alcohol consumption on cancer risk is due to bacterial metabolism of alcohol to acetaldehyde in saliva. Orally administered acetaldehyde produced increased cell proliferation in the tongue, epiglottis, and forestomach in Wistar rats; cell differentiation was not affected. Homann et al. cite previous research suggesting that bacteria can metabolize ethanol to acetaldehyde in the upper gastrointestinal tract and that oral bacteria can produce substantial amounts of acetaldehyde, which remains present in saliva for a long time. Homann et al. concluded that bacterially produced acetaldehyde in saliva may be an explanation for the tumorpromoting effect of alcohol on upper gastrointestinal tract epithelia. These two articles together paint an interesting picture of the possible mechanisms underlying the association between alcohol consumption and risk of oral cancers. At least two types of mechanisms may be involved: 1) genetic variation in speed of metabolizing ethanol to acetaldehyde and 2) variation in oral microorganisms. But these factors are related to just one step in the pathway. Another important inherited factor specific to alcohol consumption is speed of metabolizing acetaldehyde to acetate. In addition, factors that reduce oxidative damage (e.g., dietary antioxidants), permit efficient repair of DNA damage before cell replication, or improve recognition and destruction of malignant cells will modify cancer risk related to alcohol intake. Knowledge about underlying biologic mechanisms can lead us to better interventions for cancer prevention, early detection, and treatment, but uncertainty about these mechanisms does not preclude development of effective interventions. Do we need to know the mechanisms underlying the association between alcohol consumption and oral cancers to change oral cancer risk?