Association between head and neck cancer and microsomal epoxide hydrolase genotypes

Abstract

Tobacco-associated carcinogens are catalyzed by microsomal epoxide hydrolase (mEH). Combinations of the Y113H and H139R polymorphic EPHX1 variants have been assumed to alter the enzyme activity and thus the risk of squamous cell head and neck cancer (SCCHN). Based on in vitro data, a putative low, medium and high mEH activity has been associated with combinations of these genotypes, and the respective activity categories have been frequently used in the estimation of risks for smoking-related cancers. We investigated the SCCHN risk for EPHX1 genotypes among 280 cases and 289 controls. We could not detect main effects of the EPHX1 genotypes, but a smaller risk of the 139HR genotype in smokers (odds ratio, OR, 0.57; 95% confidence interval, CI, 0.34-0.95). We could not confirm an increase of the SCCHN risk for genotype combinations according to a putative medium and high enzyme activity (OR 1.28, 95% CI 0.84-1.96; OR 0.98, 95% CI 0.58-1.64, respectively), but a significant heterogeneity of the estimated risks for the singular genotypes within these categories among smokers ( P=0.02). Further, p53 mutations among smoking cases were less frequent in the group with a putative high enzyme activity, although insignificant due to small numbers (OR 0.54, 95% CI 0.13-2.17). This supports uncertainties in categorizing genotypes with respect to limited enzyme activity data, especially when taken from in vitro experiments.

CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer

“…A recent meta-analysis reported a modest positive association between SCCHN and CYP1A1 3Ј-Xanking region and Glutathione S-transferase (GSTs, phase II enzymes) polymorphisms (Hashibe et al 2003), while some studies have demonstrated a slight association with N-acetyltransferase 2 (NAT2) slow variant (phase II enzyme) (Gajecka et al 2005;Gonzalez et al 1998;Morita et al 1999). Nevertheless other studies have produced inconsistent results for CYP2E1 RsaI and DraI (Li et al 2005), and microsomal Epoxide Hydrolase (mEH, phase I enzyme) polymorphisms (Wenghoefer et al 2003;To-Figueras et al 2002;Jourenkova-Mironova et al 2000).…”

Genetic polymorphisms and head and neck cancer risk (Review)

“…Five (83%) ORs (73,92,103,104) from 6 studies (37,73,92,103,104) (Table II). Alcohol consumption is classified as a risk factor for HNC according to data from epidemiologic studies (6).…”

“…The EPHX1 His113 variant shows a 40% decrease in EH activity, whereas the EPHX1 Arg139 variant shows 25% increased enzyme activity (246). These polymorphic alleles have been linked to increases in risk for lung (247), colon (248) and ovarian (249) cancers.Five (83%) ORs (73,92,103,104) from 6 studies (37,73,92,103,104) (Table II). Alcohol consumption is classified as a risk factor for HNC according to data from epidemiologic studies (6).…”

Meta-analysis and pooled analysis of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers: a HuGE-GSEC review

“…The bibliographic search led to the identification of 56 original articles. Of these, five did not include data on the genes involved in this analysis, [45][46][47][48][49] three did not provide the data that was needed to calculate the ORs for oral and pharyngeal sites, 50 -52 therefore were not further evaluated. Of the remaining 48 articles, 18 were excluded from the meta-analysis because they did not provide head and neck subsite specific data and subjects with laryngeal tumors were not distinguished from the oral/pharyngeal group.…”