Abstract
Alcohol consumption interacts with tobacco use to increase the risk of head and neck squamous cell carcinoma (HNSCC). Alcohol is eliminated through oxidation by alcohol dehydrogenase (ADH). The ADH1C gene is polymorphic and the ADH1C*1 allele metabolizes ethanol to acetaldehyde at a higher rate than the variant ADH1C*2 allele. This polymorphism has been reported to alter the risk of HNSCC associated with alcohol use, although the literature differs in the estimates of both the magnitude and direction of this effect modification. We have investigated the association between the established risk factors for HNSCC and variant genotypes of ADH1C in a case-control study in the greater Boston area. ADH1C genotypes were determined from 521 cases and 599 population-based controls. The odds ratio (OR) for HNSCC associated with >26 drinks per week was 3.7 [95% confidence interval (95% CI), 2.4-5.7], whereas the OR for smoking >58 pack-years was 5.6 (95% CI, 3.8-8.4). The combination of heavy smoking and heavy drinking significantly interacted to produce an OR of 17.3 (95% CI, 7.8-38.3). In cases and controls, respectively, 16% and 14% were ADH1C*1-1, 46% and 46% were ADH1C*1-2 and 38% and 40% were ADH1C*2-2. There was a significant interaction of alcohol use and genotype (P = 0.05), with an estimated oral cancer risk in heavy drinkers of 7.1 (95% CI, 2.3-22.0) for homozygous variants compared with an OR of 2.3 (95% CI, 1.4-3.8) for ADH1C homozygous wild type or heterozygous individuals (controlling for smoking, age, race, and gender). These findings suggest that the ADH1C*2-2 genotype is associated with susceptibility to smoking and drinking-related HNSCC by modifying the biologically effective dose of alcohol.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the 10th most common cancer in the United States
We observed a significant interaction between heavy alcohol consumption and cigarette smoking resulting in an elevated HNSCC risk
In evaluating the extent to which the ADH1C polymorphism modifies the HNSCC risk, we observed a significant interaction between the ADH1C variant genotype and alcohol consumption such that the ADH1C*2-2 genotype conferred a large, significant elevation in HNSCC risk among the heavier alcohol drinkers (z30 drinks/wk)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the 10th most common cancer in the United States. HNSCC is the sixth most common cancer for both sexes and the third most common cancer in developing nations [1]. The use of tobacco and alcohol accounts for f75% of all HNSCCs in the United States [2, 3]. Rothman [4] and Blot et al [5] have shown that alcohol and tobacco have both independent and synergistic roles in the genesis of HNSCC. There is a strong dose-response relationship for both alcohol and tobacco consumption in virtually all of the HNSCC studies published to date. The well-established synergy between tobacco and alcohol suggests that much of alcohol’s carcinogenic action involves the enhancement of the well-known carcinogenic effect of tobacco
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