title: Microsomal epoxide hydrolase (EPHX1), slow (exon 3, 113His) and fast (exon 4, 139Arg) alleles confer susceptibility to squamous cell esophageal cancer.
abstract: Genetic polymorphisms in xenobiotic metabolizing enzymes may alter risk of various cancers. Present case-control study evaluated the influence of EPHX1 genetic variations on squamous cell esophageal cancer (ESCC) susceptibility in 107 patients and 320 controls. EPHX1 polymorphic alleles were genotyped by direct sequencing (exon 3, Tyr113His) or PCR-RFLP (exon 4, His139Arg). Patients with exon 3 genotypes (Tyr113His, His113His) and 113His allele were at risk of ESCC (OR(Tyr113His) 2.0, 95% CI=1.2-3.4, p=0.007; OR(His113His) 2.3 95% CI=1.0-5.2, p=0.03 and OR(His) 1.5, 95% CI=1.0-2.1, p=0.01). In contrast, individuals with exon 4, 139Arg allele were at low risk of cancer (OR 0.34, 95% CI=0.20-0.56, p=0.001). However, none of haplotype combinations of exon 3 (Tyr113His) and exon 4 (His139Arg) polymorphisms showed modulation of risk for ESCC. Sub-grouping of patients based on anatomical location of tumor predicted that patients with exon 3, His113His and Tyr113His genotypes were at higher risk for developing ESCC tumor at upper and middle third locations (OR 4.4, 95% CI=1.0-18.5, p=0.04; OR 2.5, 95% CI=1.3-5.0, p=0.005 respectively). The frequency of exon 4, His139Arg genotype was significantly lower in ESCC patients with lower third tumor location as compared to controls (14.8% vs. 36.3%, p=0.02). In case-only study, gene-environment interaction of EPHX1 genotypes with tobacco, alcohol and occupational exposures did not appear to modulate the cancer susceptibility. In conclusion, exon 3, Tyr113His genotype was associated with higher risk of ESCC particularly at upper and middle-third anatomical locations of tumor. However, His139Arg genotype of exon 4, exhibited low risk for ESCC as well as its clinical characteristics.
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow-226014, India.
authors.forename: Meenu
authors.initials: M
authors.lastname: Jain
authors.forename: Anup Raj
authors.initials: AR
authors.lastname: Tilak
authors.forename: Rohit
authors.initials: R
authors.lastname: Upadhyay
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kumar
authors.forename: Balraj
authors.initials: B
authors.lastname: Mittal
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000453:epidemiology; D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D004781:Environmental Exposure; D004851:Epoxide Hydrolases / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008875:Middle Aged; D016273:Occupational Exposure; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D012306:Risk; D012907:Smoking / Q000453:epidemiology
chemical_list: D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human