title: COMT polymorphisms affecting protein expression are risk factors for endometrial cancer.
abstract: In estrogen metabolic pathways, the COMT enzyme is related to detoxification. COMT gene polymorphisms have been shown to effect enzyme function. We hypothesized that these polymorphisms may be risk factors for endometrial cancer (EC). DNA samples from 150 cases of EC and healthy controls (n = 165) were analyzed by PCR-RFLP to determine the genotypic frequency of four different polymorphic loci on COMT [codon 62 (rs4633), 102 (rs5031015), 136 (rs4818), 158 (rs4680)]. Genotyping was confirmed by direct DNA sequencing. We also conducted haplotype analysis of COMT and investigated the relationship between COMT expression and COMT SNPs in EC tissues by immunohistochemistry. A significant increase in the T/T genotype of codon 62 (C/T) was observed in patients compared to controls (OR = 2.39, 95% CI: 1.31-4.37, P = 0.004). The frequency of the C-G haplotype of codon 62 C/T and codon 158 G/A was significantly higher in controls (P < 0.0001) than in patients. The expression level of COMT protein in EC tissues was significantly lower in COMT codon 62 variant TT and codon 158 variant AA genotype carriers. Therefore, the EC samples with polymorphic variants of COMT lead to lower expression of COMT protein whereas EC samples with wild-type codon 62 C/C and codon 158 G/G have higher expression of COMT protein. This is the first study demonstrating that polymorphisms in COMT codon 62 and codon 158 altered protein expression levels in EC, suggesting that they may be risk factors for EC in Caucasians.
authors.affiliation: Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hinoda
authors.forename: Naoko
authors.initials: N
authors.lastname: Okayama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suehiro
authors.forename: Ken
authors.initials: K
authors.lastname: Kawamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kikuno
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rabban
authors.forename: Lee-May
authors.initials: LM
authors.lastname: Chen
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D017931:DNA Primers; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors
chemical_list: D017931:DNA Primers; D002394:Catechol O-Methyltransferase