Microsomal epoxide hydrolase polymorphism as a risk factor for ovarian cancer

Abstract

Microsomal epoxide hydrolase (EPHX) is one of many enzymes involved in the metabolism of endogenous and exogenous toxicants. Polymorphic forms of the human EPHX gene have been described that vary in enzymatic activity, and one, Tyr113His, has been associated with hepatocellular carcinoma susceptibility. We demonstrated that EPHX was highly expressed in the human ovary, and investigated whether specific EPHX genotypes are associated with ovarian cancer susceptibility. Seventy-three Caucasian patients with ovarian cancer and 75 Caucasian-female controls without cancer were genotyped for the Tyr113His polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the homozygous high-activity genotype was 41% in the control population and 64% in the ovarian cancer patients. The odds ratio for ovarian cancer with this genotype was 2.6 (95% confidence interval 1.3, 5.0; P < 0.01). The increased ovarian cancer risk associated with the high-activity genotype could reflect differences in metabolic activation of endogenous or exogenous carcinogens.

The microsomal epoxide hydrolase Tyr113His polymorphism: Association with risk of ovarian cancer

“…Our ®ndings contrast with the original association reported by Lancaster et al [9], which indicated from a study of 73 cases and 75 controls that the TT genotype was associated with a signi®cantly increased risk of ovarian cancer overall. The much larger size of our study provided 80% power to detect an OR of 1.6, considerably lower than that of 2.6 reported by Lancaster et al [9].…”

“…The much larger size of our study provided 80% power to detect an OR of 1.6, considerably lower than that of 2.6 reported by Lancaster et al [9]. Lancaster et al [9] provided no information on the clinical presentation of their cases, so we are unable to examine their data by histologic or other subgroup.…”

“…The much larger size of our study provided 80% power to detect an OR of 1.6, considerably lower than that of 2.6 reported by Lancaster et al [9]. Lancaster et al [9] provided no information on the clinical presentation of their cases, so we are unable to examine their data by histologic or other subgroup. We believe that our control group genotype frequencies are representative because there was no signi®cant difference in the control group frequencies of the two studies (P 0.4) or between the present control group and a series of 547 younger controls collected as part of an Australian breast cancer case-control study (P 0.7; unpublished data).…”

Variant metabolizing gene alleles determine the genotoxicity of benzo[a]pyrene

“…Therefore, the variant alleles can have increased or reduced associations with cancer. For example, EH3* is shown to be associated with the reduced CA (our data) and DNA adducts [Pastorelli et al, 1998] from BP, but it is associated with increased ovarian [Lancaster et al, 1996] and colon cancer [Harrison et al, 1999]. The latter association may be the result of alternative metabolizing activities of the EH enzymes regarding other environmental carcinogens [Hassett et al, 1997;Norppa, 2000].…”

Xenobiotic‐Metabolizing gene polymorphisms and ovarian cancer risk

“…This change is predicted to be damaging to the function of epoxide hydrolase [16] and has been shown to alter epoxide hydrolase's processing of several carcinogens [17][18][19]. Genotypes at this SNP have been studied previously in relation to ovarian cancer risk in two smaller study populations [20,21], and association with risk was observed in one study (OR 2.6, 95% CI: 1.3 -5.0) [20]. The modest EPHX1 rs1051740 risk estimate we observed may only be apparent with large sample size.…”