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

Estrogen production and metabolism play critical roles inthe development and pathogenesis of endometrial carci-noma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in theestrogen metabolism pathway that result in the hydroxyla-tion and conjugation of estradiol, respectively. We evalu-ated the association between the CYP1B1 Leu432Valand CYP1B1 Asn453Ser polymorphisms and the COMTVal158Met polymorphism and invasive endometrial cancerriskinacase-controlstudynestedwithintheNurses’HealthStudy (n ‹222 cases, 666 controls). We also evaluatedwhether body mass index (BMI), postmenopausal hormone(PMH) use and cigarette smoking modified the associationsof the CYP1B1 and COMT genotypes and endometrialcancer risk. Conditional logistic regression was used tocalculate the adjusted odds ratios (OR) and 95% confi-dence intervals (CI) to quantify the risk of endometrialcancer among subjects who had at least one variant allelecompared with subjects who were homozygous for thewild-type allele. Carriers of the CYP1B1 Ser allele had astatistically significant decreased risk of endometrialcancer (OR ‹0.62; 95% CI, 0.42-- 0.91); there was nosignificant association between the CYP1B1 Val allele andendometrial cancer risk (OR ‹1.10; 95% CI, 0.75-- 1.59).Compared with the COMT Val/Val wildtype genotype, theadjusted OR of endometrial cancer for women with theCOMT Val/Met or COMT Met/Met genotype was 0.96 (95%CI, 0.65-- 1.43). We did not observe any effect modificationby BMI, PMH use and cigarette smoking for the CYP1B1and COMT genotypes. Our data suggest, that the CYP1B1Ser allele may decrease endometrial cancer risk by alteringthe production of catechol estrogens. However, furtherstudies are warranted to elucidate the role of CYP1B1 inendometrial cancer.IntroductionThe production and metabolism of estrogen play critical rolesin the pathogenesis and development of hormone-related can-cers, including endometrial carcinoma. Inherited variability inthe synthesis and metabolism of steroid hormones may affectcancer risk by contributing to individual differences in serumand cellular levels of steroidal parent hormones and hormonemetabolites (1,2). Polymorphisms in estrogen-metabolizinggenes may cause alterations in their biological function andthus potentially contribute to individual disease susceptibil-ities. We hypothesized that functionally relevant polymorph-isms in COMT and CYP1B1 may display individual, as well asadditive, effects on endometrial cancer susceptibility.Cytochrome P450 1B1 (CYP1B1) is a phase I enzyme thatcatalyzes the conversion of 17b-estradiol (E2) to the catecholestrogens,4-hydroxyestradiol(4-OH-E2)and2-hydroxyestradiol(2-OH-E2) and is involved in the activation of polycyclicaromatic hydrocarbons (3). Several single nucleotide poly-morphisms have been identified in CYP1B1. The CYP1B1Leu432Val and Asn453Ser polymorphisms located in exon 3,which encodes the catalytically important heme-bindingdomain of the enzyme, were selected as candidate susceptibil-ity alleles (4,5). These polymorphisms are biologically rele-vant and functional (6-- 9), and have been studied in relation toother hormonally relevant cancers, such as breast cancer(5,10-- 12). Two additional polymorphisms, Arg48Gly andAla119Ser, also result in amino acid substitutions and aretightly linked (4). However, McLellan et al. (13) observed nokinetic differences in E2 hydroxylation activities, and con-cluded that these amino acid substitutions led to similar cata-lytic properties to those of the wildtype genotype. All CYP1B1variants form 4-OH-E2 as their main product (6,8). Hannaet al. (8) determined that inherited CYP1B1 variants dis-played higher estradiol 2- and 4-hydroxylation activitiescompared with their wildtype enzyme. Furthermore, the ratioof product formation of 4-OH-E2 to 2-OH-E2 was higherfor CYP1B1 variants compared with their wildtype counter-part (6,8), potentially contributing to higher tissue levels of4-OH-E2 (8).Catechol-O-methyltransferase (COMT) is a phase II enzymethat is involved in the conjugation and inactivation of catecholestrogens (14). COMT catalyzes the methylation of catecholestrogens to less polar monomethyl ethers. O-Methylationincreases the concentrations of 4-methoxyestradiol (4-MeO-E2) and 2-methoxyestradiol (2-MeO-E2): 2-MeO-E2 pos-sesses anti-proliferative, cytotoxic and apoptotic activitytherefore decreasing the potential for DNA damage (15-- 19).Lachman et al. (20) identified a functional polymorphism inthe COMT gene, a G!A transition at codon 158 in exon 4,leading to a substitution of methionine for valine that results ina thermolabile enzyme with reduced activity. Individuals whoare homozygous for this low activity Met allele have a 3-- 4-fold decrease in activity, resulting in possible increased levels