Microsomal epoxide hydrolase polymorphism and susceptibility to ovarian cancer.

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.