EPHX1 polymorphisms do not modify esophageal carcinoma susceptibility in Dutch Caucasians

Abstract

Abstract. Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.

EPHX1 Tyr113His and His139Arg polymorphisms in esophageal cancer risk: a meta-analysis

“…Our search strategy and inclusion criteria (the publication selection process is shown in Figure 1), 8 studies were identified with full-text articles that remained with association between EPHX 1 (Tyr113His and His139Arg) polymorphisms and EC (Zhang et al, 2003;Wang et al, 2003;Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012). Among the included articles, 7 articles provided separate data for the EPHX1 Tyr113His and EPHX1 His139Arg polymorphisms Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012), which were treated as 2 separate studies.…”

“…Among the included articles, 7 articles provided separate data for the EPHX1 Tyr113His and EPHX1 His139Arg polymorphisms Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012), which were treated as 2 separate studies. Finally, 8 articles including a total of 1158 cases and 1868 controls included studies of the Tyr113His polymorphism, whereas 7 articles including 901 cases and 1615 controls included studies of the His139Arg polymorphism.…”

Meta-analysis demonstrates lack of an association of microsomal epoxide hydrolase 1 polymorphisms with esophageal cancer risk

“…Further application of our inclusion/exclusion criteria left 9 articles (Zhang et al, 2003;Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Wang et al, 2003Wang et al, , 2006Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012), including 8 studies for the Tyr113His polymorphism with 1158 EC cases and 1868 controls Zhang et al, 2003;Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012), and 7 studies for His139Arg with 901 EC and 1615 controls Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012). The detailed selection process and the baseline characteristics of the qualified studies are presented in Figure 1 and Table 1, respectively.…”

“…Considering the fact that ethnicity differences may bias the overall estimates, we therefore conducted separate analyses based on ethnicity, where we classified 8 study populations into Chinese Zhang et al, 2003;Lin et al, 2006), Caucasians (Casson et al, 2003(Casson et al, , 2006Dura et al, 2012), and Indians (Jain et al, 2008;Ihsan et al, 2010). As shown in Table 2, albeit nonsignificant, comparison of 113Tyr versus 113His generated a weakly protective tendency for EC in Chinese (OR = 0.87; 95%CI = 0.59-1.29; P = 0.495), Caucasians (OR = 0.86; 95%CI = 0.57-1.30; P = 0.477), and Indians (OR = 0.83; 95%CI = 0.57-1.22; P = 0.352), Similar tendencies were noted for other genetic models except for Caucasians in the recessive model (OR = 1.01; 95%CI = 0.52-1.98; P = 0.976) ( Table 2).…”

“…Variations in enzyme activity of EPHX1 as a result of such polymorphisms may lead to interindividual variations in susceptibility to chemical carcinogen-induced cancers, including EC. Although some studies have attempted to link EPHX1 gene Tyr113His and His139Arg polymorphisms to EC, the resulting data are not often reproducible (Zhang et al, 2003;Casson et al, 2003Casson et al, , 2006Lin et al, 2006;Wang et al, , 2006Jain et al, 2008;Ihsan et al, 2010;Dura et al, 2012). As a caveat, failure of replication may result from the genetic heterogeneity between different races or ethnicities, as well as individual studies with relatively low statistical power.…”