Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility

• Published in: Carcinogenesis (New York) Vol. 25; no. 4; pp. 559 - 565
• Main Authors: McGrath, Monica, Hankinson, Susan E., Arbeitman, Lori, Colditz, Graham A., Hunter, David J., De Vivo, Immaculata
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2004; Oxford Publishing Limited (England)
• Subjects: 17β-estradiol; 2-hydroxyestradiol; 2-OH-E2; 4-hydroxyestradiol; 4-OH-E2; Adult; Amino Acid Substitution; Aryl Hydrocarbon Hydroxylases - genetics; Biological and medical sciences; BMI; body mass index; Carcinogenesis, carcinogens and anticarcinogens; Case-Control Studies; Catechol O-Methyltransferase - genetics; catechol-O-methyltransferase; COMT; confidence interval; CYP1B1; Cytochrome P-450 CYP1B1; cytochrome P450 1B1; Disease Susceptibility; Endometrial Neoplasms - enzymology; Endometrial Neoplasms - epidemiology; Endometrial Neoplasms - genetics; Female; Humans; likelihood ratio test; LRT; Medical sciences; Middle Aged; Mutation, Missense; NHS; Nurses' Health Study; odds ratio; PMH; Polymorphism, Genetic; postmenopausal hormones; Reference Values; standard deviation; Tumors; Methyltransferases; Enzyme; Transferases; Cytochrome P450; Pyrocatechol; Malignant tumor; Polymorphism
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgh039

Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42–0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75–1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65–1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.