Catechol-O-methyltransferase Gene Polymorphisms in Benign Prostatic Hyperplasia and Sporadic Prostate Cancer

Abstract

Various carcinogenic metabolites, including catechol estrogens, play a role in malignant transformation. An enzyme that is capable of neutralizing the genotoxic effects of these compounds is catechol-O-methyltransferase (COMT). A variant form of this enzyme has been shown to reduce its activity by up to 4-fold; thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for benign prostatic hyperplasia (BPH) and prostate cancer. To test this hypothesis, the genetic distribution of three different COMT polymorphisms at codon 62 (C!T), codon 72 (G!T), and codon 158 (G!A) were analyzed in 131 normal healthy subjects, 134 BPH, and 178 sporadic prostate cancer samples from a Japanese population. Results of these experiments show that the variant genotype at codon 62 (P = 0.060) and codon 158 (P = 0.047) are risk factors for prostate cancer but not BPH when compared with normal controls. Odds ratio (OR) and 95% confidence interval (95% CI) for cancer were 3.24 and 1.38 to 7.61, respectively, for codon 62 T/T genotype when compared with wild type. At codon 158, the A/A variant for cancer had an OR of 3.00 with a 95% CI of 1.38 to 6.54 compared with wild type. Codons 62 and 158 were in linkage disequilibrium (LD), and when compared with the C-G haplotype, other types (C-A, T-G, T-A) were observed to be associated with prostate cancer (P = 0.040) but not BPH. Codon 72 on the other hand, was not in LD with either codon 62 or 158. The homozygous variant on codon 72 was rare in this Japanese population, and the heterozygous G/T at this codon was not associated with either prostate cancer or BPH. When evaluating the risk of COMT polymorphisms with stage or grade of cancer, no associations were observed for any of the genotypes with the exception of a tendency (P = 0.096) for the variant A allele on codon 158 to be correlated with higher stages (zT 3 ) of cancer. This is the first report that shows the polymorphisms of COMT to be associated with sporadic prostatic carcinogenesis. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(2):238 -44)

Risk for Premenstrual Dysphoric Disorder Is Associated with Genetic Variation in ESR1, the Estrogen Receptor Alpha Gene

“…We selected these genes for two reasons: 1) our prior demonstration of the triggering of affective dysregulation in women with PMDD when exogenous estradiol was administered in the context of GnRH agonist-induced hypogonadism ; 2) recent studies identifying the importance of ER beta in animal models of anxiety and depression (Walf et al 2004;Krezel et al 2001;Rocha et al 2005) and of estrogen receptor alpha in arousal (Garey et al 2003). In addition, we examined associations with the Val158Met SNP (rs4680) in the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estradiol metabolism, implicated in sex hormone-mediated cancer (Tanaka et al 2006;Sazci et al 2004), and observed in other studies to regulate activity in the prefrontal cortex, a brain region implicated as dysfunctional in PMDD (Rubinow et al in press). …”

Change of COMT Val158Met Genotype in Tumoral B Cells of a Chronic Lymphocytic Leukemia Patient: A Case Report

“…This ubiquitous enzyme can be found in almost all mammalian tissues and it has a wide range of substrates, including endogenous catecholamines and catechol estrogens, but also exogenous compounds, such as certain dietary flavonoids [6-8,11,12]. The COMT gene is located on chromosome 22q11.2 and it encodes two different enzyme forms, a 221 amino acid length cytoplasmic protein and a membrane-bound form that contains additional 50 amino acid residues [6,7,13,14]. The most of the COMT occurring in human tissues is cytoplasmic [6,8,10,15,16].…”

“…The most of the COMT occurring in human tissues is cytoplasmic [6,8,10,15,16]. However, COMT enzyme is polymorphic and its activity has significant differences among individuals [8, [14][15][16][17][18][19][20]. The single nucleotide polymorphism (SNP) G>A (rs4680) leads to an amino acid change of Val to Met in the position 108/158 in cytoplasmic/ membranous enzyme form, Submit your Manuscript | www.austinpublishinggroup.com respectively, and is generally known as Val158Met.…”

“…The single nucleotide polymorphism (SNP) G>A (rs4680) leads to an amino acid change of Val to Met in the position 108/158 in cytoplasmic/ membranous enzyme form, Submit your Manuscript | www.austinpublishinggroup.com respectively, and is generally known as Val158Met. This SNP has important (two-to fivefold) impact on the enzymatic activity as those individuals homozygous for the Val (GG) have high activity enzyme variant, those with Met/Met (AA) possess low activity protein and heterozygous genotype carriers (Val/Met, GA) have the enzyme form with intermediate activity [7,12,14,17,[19][20][21][22][23][24][25][26][27][28]. It means that alteration in the respective genotype leads to the change in efficacy of O-methylation of different endogenous and exogenous catecholic compounds (including for example catechol estrogens, but also flavonoids like quercetin, fisetin and different flavanols) and therefore also to the increased amounts of circulating catechols with significantly different bioactivities compared to their O-methylated metabolites.…”

“…It is well known that hydroxylated intermediates of estradiol (2-and 4-hydroxylated estradiols) can be oxidated to highly reactive semiquinones and quinones which may induce DNA damage and cause therefore cancer development [15][16][17][18][19][20][21]25,[29][30][31][32]. These harmful effects are contravened by detoxification enzymes, mainly by COMT that catalyzes O-methylation of different catechols and facilitates their excretion from the body [14,20]. It is clear that changes in the enzymatic activity of COMT caused by Val158Met polymorphism may be implicated in carcinogenesis.…”