title: Microsomal epoxide hydrolase polymorphism and susceptibility to ovarian cancer.
abstract: Polymorphic variants of microsomal epoxide hydrolase (mEPHX) with altered enzyme activity have been associated with an increased risk for ovarian cancer. We assessed the frequency of exon 3 and exon 4 variants of mEPHX among 291 ovarian cancers and 257 controls from a UK-based population. The distribution of the exon 3 alleles among both the cancer and control groups was significantly different from that expected under Hardy-Weinberg equilibrium suggesting that the PCR restriction fragment length polymorphism (PCR-RFLP) genotyping assay might be flawed. The codon 113 polymorphism was reassessed using a two-color allele-specific PCR-based assay. We found that a codon 119 G>A polymorphism, present in 20% of the British population and linked to the wild-type exon 3 allele, resulted in some Tyr113/His113 heterozygotes being falsely classified as His113/His113 homozygotes when using the PCR-RFLP assay. Consequently, we reassessed all our codon 113 data using the new allele-specific assay. We found no evidence of an association of ovarian cancer risk with the exon 3 Tyr113>His113 variant. Similarly the frequencies of the exon 4 His139>Arg139 genotypes were not significantly different between cases and controls. Stratifying the genotyping data according to the predicted mEPHX activity revealed a highly significant decrease in high mEPHX activity among the serous ovarian cancers (P=0.01) suggesting that high mEPHX activity may be protective for this histological sub-type. Furthermore previous disease association studies of exon 3 alleles which utilized the PCR-RFLP assay may be compromised by the existence of a codon 119 G>A polymorphism which may be common in Caucasian populations.
authors.affiliation: VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Institute, Locked Bag No. 1 A'Beckett Street, Melbourne, Victoria, 8006, Australia.
authors.forename: S W
authors.initials: SW
authors.lastname: Baxter
authors.forename: D Y H
authors.initials: DY
authors.lastname: Choong
authors.forename: I G
authors.initials: IG
authors.lastname: Campbell
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000201:enzymology / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics; D016022:Case-Control Studies; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology / Q000235:genetics; D017931:DNA Primers; D004198:Disease Susceptibility; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008861:Microsomes / Q000201:enzymology*; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012189:Retrospective Studies
chemical_list: D017931:DNA Primers; D004851:Epoxide Hydrolases