Role of alcohol dehydrogenase 3 and cytochrome P-4502E1 genotypes in susceptibility to cancers of the upper aerodigestive tract

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) can cers, but the mechanism by which alcohol causes cancer remains obscure. Eth anol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcoh ol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity, The hypot hesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH(3) and CYP2E 1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral c avity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 co ntrols, all French Caucasians, Cancer risks and gene-alcohol interactions w ere analyzed by unconditional logistic regression, accounting for potential confounders. ADH(3) genotype was not associated with UAT cancer. In contra st, a 2-fold risk of oral cavity/pharyngeal (OR = 2.0, 95% CI 1.0-3.9) and laryngeal (OR = 1.8, 95% CI 1.0-3.5) cancers was observed for carriers of t he CYP2E1 DraI C variant allele compared with other individuals. The risk a ssociated with the CYP2E1 RsaI c2 variant allele also increased for oral ca vity/pharyngeal cancer (OR = 2.6, 95% CI 1.0-6.6), The effects of ADH(3) or CYP2E1 genotype and alcohol or tobacco were independent. The highest risk of oral cavity/pharyngeal cancer was observed among the heaviest drinkers ( >80 g/day) with the CYP2E1 DraI C allele (OR = 5.8, 95% CI 1.9-18.2) or the CYP2E1 RsaI c2 allele (OR = 7.2, 95% CI 1.4-38.2) compared with lighter dr inkers with other genotypes, Our study suggests that CYP2E1 genotype modifi es the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings. (C) 2000 W iley-Liss, Inc.