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

Functional significance has been demonstrated in vitro for the exon 3 T-->C Tyr113His amino acid substitution polymorphism of the microsomal epoxide h ydrolase (EPHX) gene. The higher activity or fast TT genotype was previousl y reported to be associated with an increased risk of ovarian cancer, and t his association may reflect enhanced activation of endogenous or exogenous substrates to more reactive and mutagenic derivatives. Components of cigare tte smoke are examples of exogenous substrates subject to such bioactivatio n, and smoking exposure may thus modify the risk associated with the EPHX p olymorphism. We examined 545 cases of epithelial ovarian cancer and 287 una ffected controls for this EPHXT-C genetic variant to investigate whether, i n the Australian population, the TT genotype was associated with (i) specif ic ovarian tumor characteristics; (ii) risk of ovarian cancer, overall or f or specific subgroups; and (iii) risk of ovarian cancer in smokers specific ally. Genotyping was carried out using the Perkin-Elmer ABI Prism 7700 Sequ ence Detection System for fluorogenic polymerase chain reaction allelic dis crimination. Stratification of the ovarian cancer cases according to tumor behavior (low malignant potential or invasive), grade, stage, and p53 immun ohistochemical status failed to show any heterogeneity with respect to the genotype defined by the EPHX polymorphism. There was a suggestion of hetero geneity with respect to histologic subtype (P= 0.03), largely due to a decr eased frequency of the TT genotype in endometrioid tumors. EPHX genotype di stribution did not differ significantly between unaffected controls and ova rian cancer cases (overall, low malignant potential, or invasive) either ov erall or after stratification by smoking status. However, the TT genotype w as associated with a decreased risk of invasive ovarian cancer of the endom etrioid subtype specifically (age-adjusted odds ratio = 0.38, 95% confidenc e interval=0.17-0.87). The results suggest that the proposed EPHX-mediated bioactivation of components of cigarette smoke to mutagenic forms is unlike ly to be involved in the etiology of ovarian cancer in general but that a g reater rate of EPHX-mediated detoxification may decrease the risk of endome trioid ovarian cancer. (C) 2001 Wiley-Liss, Inc.