Polymorphisms of Catechol-O-Methyltransferase in Men with Renal Cell Cancer

Abstract

The estrogen metabolite, 4-hydroxy-estrogen, has been shown to play a role in malignant transformation of male kidneys. To counteract the effects of this catechol-estrogen, the catechol-O-methyltransferase (COMT) enzyme is capable of neutralizing the genotoxic effects of this compound. A polymorphic variant of COMT has been shown to have a reduced enzyme activity, and thus, we hypothesize that single nucleotide polymorphisms of the COMT gene can be a risk factor for renal cell cancer (RCC). To determine this hypothesis, a study of a Japanese male population was used and the genetic distributions of COMT polymorphisms at codons 62 (C!T), 72 (G!T), and 158 (G!A) were analyzed in 157 normal healthy subjects and 123 sporadic RCC (clear cell type) samples by using a sequence-specific PCR technique. These experiments show that the variant genotype (P = 0.025) and allele (P = 0.011) at codon 62 is a risk factor for RCC. The odds ratio and 95% confidence interval for cancer were 3.16 and 1.29 to 7.73, respectively, for the T/T genotype as compared with wild-type. No associations for renal cancer were found at either codons 72 or 158 in this Japanese male population. However, codons 62 and 158 were observed to be in linkage disequilibrium, and haplotype analysis shows the combined forms of T-A, T-G, and C-A to be associated with RCC as compared with C-G (P < 0.001). When evaluating the risk of COMT polymorphisms with grade of cancer, no associations were observed for any of the genotypes. This study is the first to report COMT polymorphism to be associated with RCC. These results are important in understanding the role of COMT polymorphisms in the pathogenesis of RCC.

COMT polymorphisms affecting protein expression are risk factors for endometrial cancer

“…Among other cancers including prostate, renal, lung, colorectal, and ovarian cancers, this codon 62 SNP studies have been examined [14,15,21]. Tanaka et al [14,15] reported the increased frequency of the codon 62 T/T genotype in prostatic and renal cell cancers, which is consistent with our results. The most widely studied polymorphic site in COMT gene is codon 158 and several studies have focused on the codon 158 polymorphism in the COMT gene in various carcinomas.…”

“…Therefore the COMT Met variant allele may increase EC risk. A number of various cancer studies have focused on the codon 158 polymorphism in the COMT gene, but there are few studies that have investigated other polymorphic sites [14][15][16][17]. We have previously investigated other COMT SNPs including codons 62 (rs4633) and 72 (rs6267) in prostate and renal cancers in Japanese populations [14,15].…”

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

“…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.…”