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High-Activity Microsomal Epoxide Hydrolase Genotypes and the Risk of Oral, Pharynx, and Larynx Cancers¹

Unit of Cancer Epidemiology (Institut National de la Santé et de la Recherche Médicale U521), Institut Gustave-Roussy, 94805 Villejuif, France [N. J-M., S. B.]; Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, 00250 Helsinki, Finland [K. M., A. H.]; Geneva Cancer Registry, 1205 Geneva, Switzerland [C. B.]; Division of Clinical Pharmacology, University Hospital of Geneva, 1211 Geneva, Switzerland [P. D.]

Human microsomal epoxide hydrolase (mEH), encoded by the EPHX1 gene, is involved in the metabolism of tobacco carcinogens. We investigated the effect of exon 3 and 4 polymorphisms of the EPHX1 gene in 121 patients with cancers of the oral cavity/pharynx, 129 patients with cancer of the larynx, and 172 non-cancer controls, all Caucasian regular smokers. The potential modifying role of previously analyzed GSTM1, GSTM3, and GSTP1 genotypes was also examined. Compared with the putative low-activity genotypes, odds ratios (ORs) associated with predicted intermediate and high mEH activity genotypes were significantly increased for oropharyngeal cancers [OR = 1.8; 95% confidence interval (CI) = 1.0–3.3; and OR = 2.1; 95% CI = 1.0–4.5, respectively; P_trend = 0.03] and laryngeal cancers (OR = 1.7; 95% CI = 1.0–3.1; and OR = 2.4; 95% CI = 1.1–5.1, respectively; P_trend = 0.02). Moreover, a positive interaction was found between mEH activity and GSTM3 genotype for laryngeal cancer. The combined EPHX1 high activity-associated genotype and GSTM3 (AB or BB) genotype conferred a 13.1-fold risk (95% CI = 3.5–48.4) compared with the concurrent presence of the EPHX1 low activity-associated genotype and the GSTM3 AA genotype. Thus, EPHX1 polymorphisms may be one of the factors of importance in susceptibility to smoking-related cancers of the upper aerodigestive tract.

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