Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Catechol-O-methyltransferase (COMT) plays an important role in estrogen-induced cancers because COMT inactivates catechol estrogens that have cancer-promoting activities. Two promoters control the expression of human COMT isoforms: membrane-bound COMT (MB-COMT) and soluble COMT (S-COMT). We hypothesize that inactivation of MB-COMT and S-COMT is important in understanding the pathogenesis of endometrial cancer. To test this hypothesis, we investigated the methylation status and expression of two COMT isoforms in 4 endometrial cancer cell lines, 60 endometrial cancer tissues, 10 normal endometrium tissues from normal healthy controls, and 32 pairs of cancerous and normal endometrial samples from the same patients using methylation-specific PCR, methylation-specific sequencing, reverse transcription-PCR, and 5'-rapid amplification of cDNA ends. The results of this study clearly demonstrate that MB-COMT was inactivated and methylated, although S-COMT was activated and unmethylated in all endometrial cancer cell lines. The 5-aza-2'-deoxycytidine treatment restored MB-COMT expression in all cell lines. The promoter for MB-COMT was methylated in 47 of 60 cancer tissues but was unmethylated in endometrial tissues from cases without cancer. The promoter for S-COMT was unmethylated in all endometrial cancerous and normal tissues. The CpG methylation density at the MB-COMT promoter was significantly higher in cancer tissues (a mean of 79.1% of the 19 CpG sites; range, 69-94%) than in adjacent normal tissues (a mean of 8.7% of the 19 CpG sites; range, 3-14%). In summary, these findings demonstrate that methylation of multiple promoters of the COMT gene can selectively inactivate MB-COMT and may contribute to endometrial carcinogenesis.
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PMID:Multiple promoters of catechol-O-methyltransferase gene are selectively inactivated by CpG hypermethylation in endometrial cancer. 1281 Jun 35

Prolonged exposure to unopposed estrogens is a major risk factor for the development of endometrial cancer. Oxidative metabolism of estradiol (E(2)) into the catecholestrogens (CEs), 4-hydroxyestradiol (4-OHE(2)) and 2-hydroxyestradiol (2-OHE(2)), may play an important role in estrogen carcinogenicity. CEs can be oxidized to the corresponding ortho-quinone derivatives with concomitant formation of the reactive oxygen species (ROS). Catechol-O-methyltransferase (COMT) is the major enzyme involved in the detoxification of CEs in extrahepatic tissues. We investigated the potential of E(2), 2-OHE(2) and 4-OHE(2) to induce microsatellite instability (MSI) and neoplastic transformation of immortalized human endometrial glandular (EM) cells. We also investigated the functional significance of COMT gene expression on modulating the effects of E(2) and CEs in EM cells. Our data indicated that E(2) and 4-OHE(2) induce MSI, ROS and neoplastic transformation in EM cells. The capacity of E(2) and its catechol metabolites to induce MSI, ROS and neoplastic transformation in EM cells is ranked as follows: 4-OHE(2) > E(2) > 2-OHE(2). Knockdown of COMT expression in EM cells resulted in increased estrogenic milieu and increased estrogen-induced cell proliferation. More importantly, knockdown of COMT increased the propensity of E(2) or CEs to induce ROS, MSI and neoplastic transformation of EM cells. In contrast, overexpression of COMT in EM cells significantly reduced the cellular estrogenic milieu and protected against E(2)- or CEs-induced, ROS, MSI and neoplastic transformation. The capacity of E(2) or CEs to induce neoplastic transformation of human endometrial glandular cells in vitro may suggest that E(2)-induced endometrial cancer is mediated by its metabolism into CEs. Our study clearly indicates that COMT gene expression plays a critical role in modulating the hormonal and carcinogenic effects of E(2) and CEs and, consequently, modifies the risk for E(2)-induced endometrial cancer. To the best of our knowledge, this is the first study to (i) demonstrate the potential capacity of estrogen and its catechol metabolites to induce neoplastic transformation of immortalized human endometrial glandular cells; and (ii) illustrate the important role of COMT gene expression in protecting against E(2)-induced endometrial cancer.
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PMID:Catecholestrogens induce oxidative stress and malignant transformation in human endometrial glandular cells: protective effect of catechol-O-methyltransferase. 1856 89

Catechol-O-methyltransferase (COMT) is vital for the conjugation of catechol estrogens that are produced during oestrogen metabolism. The efficiency of this process varies due to a polymorphism in COMT, which changes valine to methionine (V158M). The Met genotypes slow the metabolism of catechol oestrogens, which are agents that are capable of causing DNA damage through the formation of DNA adducts and reactive oxygen species (ROS) production. The slower metabolism of catechol oestrogens results in there being a higher circulating concentration of these oeastrogens and consequently greater probability of DNA damage. To determine whether metabolic inefficiencies of oeastrogen metabolism are associated with the development of malignancy in hereditary non-polyposis colorectal cancer (HNPCC), we studied the V158M polymorphism in COMT in a large cohort of 498 HNPCC patients from Australia and Poland that were either mutation positive (n = 331) or negative (n = 167) for mismatch repair (MMR) gene mutations (hMLH1 or hMSH2). HNPCC is a familial predisposition to colorectal cancer (CRC) and extracolonic cancers that include endometrial cancer.Using Real Time PCR, the COMT V158M polymorphism was examined and its association with disease expression, age of diagnosis of cancer, mutation status and mutation type was assessed in the HNPCC MMR mutation positive and negative groups. This study showed that the V158M polymorphism had no association with disease risk in the HNPCC MMR mutation positive population. However, the polymorphism was significantly associated with endometrial/ovarian cancer risk in HNPCC MMR mutation negative patients (p = 0.002). The heterozygous (Val/Met) genotype was associated with an increased risk of developing endometrial/ovarian cancer whereas the homozygous mutant (Met/Met) showed a decreased risk. The results suggest heterosis, where there is an apparent greater effect of the heterozygous state in this dichotomous trait. In conclusion, this study shows that the COMT V158M polymorphism alters the risk of developing endometrial/ovarian cancer in patients that adhere to the Amsterdam HNPCC criteria but do not have a DNA mismatch repair gene mutation.
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PMID:The Association of the COMT V158M Polymorphism with Endometrial/Ovarian Cancer in HNPCC Families Adhering to the Amsterdam Criteria. 2022 14

Catechol-O-methyltransferase (COMT) is a critical enzyme to detoxify the carcinogenic catechol estrogen and the Val158Met polymorphism of COMT could influence its enzymatic activity. Recent epidemiological studies have investigated the correlation of COMT Val158Met polymorphism with endometrial cancer risk; however, the results are inconsistent. To better evaluate the role of COMT Val158Met in endometrial carcinogenesis, we performed this meta-analysis, considering menopausal status, study quality, ethnicity, and source of controls. Eight eligible studies including 5109 subjects were collected from PubMed, CNKI, and Chinese Biomedicine Database (updated until September 21, 2012). Although no obvious associations were detected between COMT Val158Met and endometrial cancer susceptibility in the pooled analysis, we noted significantly decreased endometrial cancer risk for Val/Met versus Val/Val, and Met/Met + Val/Met versus Val/Val genetic models in the postmenopausal female (OR = 0.795, 95%CI = 0.656-0.962, P = 0.019; and OR = 0.819, 95%CI = 0.683-0.983, P = 0.032; respectively), and similar results existed in high-quality studies (OR = 0.835, 95%CI = 0.726-0.961, P = 0.012; and OR = 0.853, 95%CI = 0.747-0.974, P = 0.019; respectively). However, no evidence of association was noted in different ethnic groups and sources of controls. In conclusion, our results suggested that the COMT Val/Val genotype might act as a potential endometrial cancer risk factor in postmenopausal women. Further studies are needed to investigate the interactions between COMT Val158Met polymorphism and endometrial cancer in a specific population.
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PMID:Contribution of catechol-O-methyltransferase Val158Met polymorphism to endometrial cancer risk in postmenopausal women: a meta-analysis. 2439 Sep 93