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

Abstract

Alcohol is a recognized risk factor for upper aerodigestive tract (UAT) cancers, but the mechanism by which alcohol causes cancer remains obscure. Ethanol is oxidized to acetaldehyde (the suspected carcinogenic agent in alcohol) by alcohol dehydrogenases (ADHs) and cytochrome P-4502E1 (CYP2E1), both of which exhibit great inter-individual variability in activity. The hypothesis that these polymorphisms influence susceptibility to alcohol-related cancers remains poorly documented. We investigated whether ADH 3 and CYP2E1 DraI and RsaI genotypes modified the risk of UAT cancers among 121 oral cavity/pharyngeal cancer patients, 129 laryngeal cancer patients, and 172 controls, all French Caucasians. Cancer risks and gene-alcohol interactions were analyzed by unconditional logistic regression, accounting for potential confounders. ADH 3 genotype was not associated with UAT cancer. In contrast, 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 the CYP2E1 DraI C variant allele compared with other individuals. The risk associated with the CYP2E1 RsaI c2 variant allele also increased for oral cavity/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 drinkers with other genotypes. Our study suggests that CYP2E1 genotype modifies the risk of UAT cancers, but due to the low frequency of CYP2E1 variant alleles, large-scale studies are needed to confirm our findings. Int.

Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk

“…37 Therefore, perhaps we should not be surprised to find multiple genetic differences between the Greek and other European populations, as well as even greater differences with populations such as those in Puerto Rico where Hispanic-Native American-African admixture has occurred. 38 As we noted in the introduction, a recent study conducted in France found no significant evidence of an effect of the ADH 3 SNP on OC risk, 24 consistent with a previous analysis of the same study subjects. 40 In contrast to the findings obtained in Puerto Rico, the effect of this SNP on OC risk did not seem to be influenced by amounts of alcohol consumed.…”

“…Evidence of this SNPs interaction with alcohol consumption in OC risk was reported in a case control study conducted in Puerto Rico. 6 By contrast, in a study recently reported using a French population, 24 no association was found with the ADH 3 SNP but an association was reported for CYP2E1.…”

Susceptibility to lung cancer and genetic polymorphisms in the alcohol metabolite‐related enzymes alcohol dehydrogenase 3, aldehyde dehydrogenase 2, and cytochrome P450 2E1 in the Japanese population

“…16,17,[32][33][34] We failed to observe an association between ADH 3 gene polymorphisms and the development of lung cancer, most likely because of the limited statistical power from the low frequency of the variant allele in the Japanese population.…”

CYP2E1 RsaIpolymorphism impacts on risk of colorectal cancer association with smoking and alcohol drinking

“…Some studies demonstrated the common genotype or alleles to confer greater risk of oral [15] , pharyngeal [15] , esophageal [16,17] liver [18] and lung [19,20] cancers. On the other hand, increased risk of oral [21] , nasopharyngeal [22] , liver [23] and colorectal [24,25] cancers was observed with the rare genotype or allele carriers in other studies.…”