Alcohol Dehydrogenase 3 and Risk of Squamous Cell Carcinomas of the Head and Neck

Donghong Wang,Thomas H Haugen,Lubomir P Turek,Zugui Zhang,Justine M Ritchie,Elaine M Smith

doi:10.1158/1055-9965.epi-04-0343

Abstract

In order to examine the association between alcohol dehydrogenase 3 (ADH3) genotypes and risk of head and neck squamous cell carcinomas (HNSCC), we conducted a hospital based case-control study including 348 cases and 330 controls. DNA isolated from exfoliated cells from the oral cavity were genotyped for ADH3 polymorphisms using PCR followed by SspI digestion. Odds ratios (OR) and hazards ratios (HR) were done by unconditional logistic regression and Cox regression. Relative to ADH3(2-2) carriers, ADH3(1-1) [OR, 0.7; 95% confidence interval (CI), 0.4-1.1] and ADH3(1-2) (OR, 0.8; 95% CI, 0.5-1.2) had a nonsignificant reduced risk of HNSCC. ADH(1-2) smokers of >30 pack-years were at decreased risk of oral cavity squamous cell carcinomas compared with ADH3(2-2) (OR, 0.3, 0.1-0.9), whereas ADH3(1-1) smokers were not. After adjustment, those with ADH3(1-2) had significantly worse overall survival compared with ADH3(1-1) (HR, 0.3, 0.2-0.6) or ADH3(2-2) (HR, 0.4, 0.2-0.9) and increased recurrence (ADH3(1-1), 0.2, 0.1-0.6; ADH3(2-2), 0.6, 0.2-1.3). Our data did not show that ADH3 genotypes had a significantly independent effect on the risk of HNSCC, nor did they modify the risks increased by alcohol or tobacco consumption and high-risk human papillomavirus infection. However, participants with ADH3(1-2) genotype were associated with poorer survival compared with those who had the other two ADH3 genotypes and a higher rate of recurrence than participants with ADH3(1-1) genotype.

Highlights

Alcohol dehydrogenase 3 (ADH3) gene loci carry two alleles coding respectively for the g1 and g2 subunits of the dimeric ADH3 enzyme. g1 and g2 subunits are different by one single amino acid, arginine for g1 and glutamine for g2 at 271
Because an association between the presence of human papillomavirus (HPV) and the development of head and neck cancer is widely accepted, and because we found that HPV had an interaction effect with alcohol in our previous study [18], we considered it important to include the HPV data in this study to evaluate whether the interaction between HPV and alcohol consumption was associated with a specific ADH3 genotype
We evaluated 348 head and neck squamous cell carcinomas (HNSCC) cases (39.9% in the oropharynx and 64.1% in the oral cavity) and 330 controls

Summary

Introduction

Alcohol dehydrogenase 3 (ADH3) gene loci carry two alleles coding respectively for the g1 and g2 subunits of the dimeric ADH3 enzyme. g1 and g2 subunits are different by one single amino acid, arginine for g1 and glutamine for g2 at 271. Alcohol dehydrogenase 3 (ADH3) gene loci carry two alleles coding respectively for the g1 and g2 subunits of the dimeric ADH3 enzyme. All five classes of ADH enzymes are responsible for the oxidation of ethanol to acetaldehyde, which mainly occurs in the liver, and the ADH3 genes belongs to ADH class I [2]. Acetaldehyde, the metabolite of alcohol oxidation, is implicated in ethanol-induced cell damage, and production of free radicals and DNA hydroxylated bases. It is mutagenic and carcinogenic in experimental animals, in short term cell culture assays [8,9,10,11,12]

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