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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.
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PMID:Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. 1910 24

The aim of our study was to evaluate the effects of 5-aza-2'-deoxycytidine (5-azadC) on cell growth inhibition, cell cycle arrest, apoptosis as well as the expression levels of hMLH1 and DNMT3B in human endometrial cancer cell lines. Ishikawa, HHUA, and KLE cell lines were used. After treatment with 5-azadC, cells were measured by MTT to detect the growth inhibition. Flow cytometry analysis was used to evaluate the cell cycle distribution and apoptosis effect. The expression of hMLH1 and DNMT3B was performed by real-time PCR and Western blotting analysis. The methylation status of the hMLH1 gene was monitored by methylation-specific PCR. We confirmed that 5-azadC treatment resulted in growth inhibition, G(2) arrest, and cell apoptosis in human endometrial cancer cell lines. Furthermore, the data obtained by real-time PCR and Western blotting analysis demonstrated that the expression of hMLH1 was up-regulated by 5-azadC treatment in Ishikawa cells, accompanied by down-regulation of DNMT3B expression, when 5-azadC led to cell inhibition, G(2)/M arrest, and apoptosis. Our results suggested that 5-azadC is a potent inhibitor of DNA methyltransferase 3B and induces apoptosis in Ishikawa cells with the up-regulation of hMLH1.
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PMID:5-Aza-2'-deoxycytidine is a potent inhibitor of DNA methyltransferase 3B and induces apoptosis in human endometrial cancer cell lines with the up-regulation of hMLH1. 1930 77

Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited disease caused by a germline mutation of the mismatch repair (MMR) genes, and the distinctive feature is that colorectal and extracolonic malignancies occur early in life. We report on the case of a Korean HNPCC family with endometrial cancer, with the goal of elucidating the involvement of an MMR deficiency. Although the family history did not fulfill the Amsterdam criteria II, blood samples were subjected to genetic testing by the revised Bethesda guidelines. Immunohistochemistry and direct sequencing of the genomic DNA identified a C insertion at the 1780th base in exon 16 of hMLH1, a pathogenic mutation that has not been reported before. By this mutation, premature termination at codon 592 resulted with an estimated deletion of 21% of the C-terminus of the hMLH1 protein. For early detection of the disease, the family was examined by colonoscopy and a gynecologic examination. The expression of hMLH1 in colon tissues was analyzed by Western blot analysis. We observed that the C-terminus portion of the hMLH1 protein was truncated in the HNPCC family members. Two young family members with no clinical symptoms were newly diagnosed with colorectal cancer by colonoscopy and a pathological examination. Hereby, we identified a novel pathogenic germline mutation of hMLH1 in a Korean HNPCC family. The loss of C-terminus of hMLH1 protein was thus considered to possibly play a role in the development of HNPCC with other tumors. Our findings might be useful for early diagnosis and management of the HNPCC family.
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PMID:A novel germline mutation of hMLH1 in a Korean hereditary non-polyposis colorectal cancer family. 1936 Mar 43

Point mutations of KRAS and BRAF genes are thought to be important in carcinogenesis of colon cancer. In particular, gene instability caused by decreased expression of the hMLH1 gene, a DNA mismatch repair (MMR) gene, may be linked to the activating BRAF V600E point mutation in sporadic colon cancer. However, a consensus has not been established regarding the correlation between point mutations of KRAS or BRAF and carcinogenesis in patients with endometrial cancer, which is closely related to colon cancer. Therefore, we analyzed aberrant hypermethylation of the hMLH1 gene, microsatellite instability (MSI), and point mutations of KRAS and BRAF in 44 samples of sporadic endo-metrial cancer, with the aim of examining the mechanism of carcinogenesis in patients with endometrial cancer. Aberrant hMLH1 hypermethylation was found in 17 of the 44 cases (38.6%) and showed a significant positive correlation with MSI (p=0.02). This suggests that an abnormal MMR mechanism plays an important role in carcinogenesis of sporadic endometrial cancer. Point mutation of KRAS was found in 6 of the 44 cases (13.6%), but no BRAF V600E mutation was detected. These data suggest that the BRAF V600E mutation is not the target gene for abnormal MMR in carcinogenesis in patients with sporadic endometrial cancer, unlike in colon cancer. This is supported by the relatively few previous reports indicating a correlation between endometrial cancer and the BRAF V600E mutation. Identification of new candidates for the target gene for abnormal MMR in endometrial cancer requires further work.
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PMID:Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer. 1942 71

Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1 expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation.
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PMID:Epigenetic DNA hypermethylation: clinical applications in endometrial cancer (Review). 1978 8

Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MSI in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MSI mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer.
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PMID:Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer. 1978 50

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Such tumors are thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene, but many aspects of the pathology of familial endometrial cancer are unclear and no effective screening method has been established. However, the pathology of endometrial cancer with familial tumor has been progressively clarified in recent studies. At present, about 0.5% of all cases of endometrial cancers meet the clinical diagnostic criteria for HNPCC. A recent analysis of the three MMR genes (hMLH1, hMSH2 and hMSH6) revealed germline mutations in 18 of 120 cases (15.0%) of endometrial cancer with familial accumulation of cancer or double cancer, with a frameshift mutation of the hMSH6 gene being the most common. Many cases with mutation did not meet the current clinical diagnostic criteria for HNPCC, indicating that familial endometrial cancer is often not diagnosed as HNPCC. The results suggest that the hMSH6 gene mutation may be important in carcinogenesis in endometrial cancer and germline mutations of the MMR gene may be more prevalent in cases associated with familial accumulation of cancer. An international large-scale muticenter study is required to obtain further information about the pathology of endometrial cancer as a familial tumor.
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PMID:Endometrial cancer as a familial tumor: pathology and molecular carcinogenesis (review). 1979 85

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

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.
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PMID:Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters. 2064 May 20

Endometrial cancer is the seventh most common cancer in women worldwide. Therefore elucidation of the pathogenesis and development of effective treatment for endometrial cancer are important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic variation and mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, in recent years, epigenetic mechanisms that do not involve changes in DNA sequences have been examined. Studies aimed at detection of aberrant DNA hypermethylation in cancer cells present in microscopic amounts in vivo and application of the results to cancer diagnosis have also started. Breakdown of the DNA mismatch repair mechanism is thought to play a large role in the development of endometrial cancer, with changes in the expression of the hMLH1 gene being particularly important. Silencing of genes such as APC and CHFR, Sprouty 2, RASSF1A, GPR54, CDH1, and RSK4 by DNA hypermethylation, onset of Lynch syndrome due to hereditary epimutation of hMLH1 and hMSH2 mismatch repair genes, and regulation of gene expression by microRNAs may also underlie the carcinogenic mechanisms of endometrial cancer. Further understanding of these issues may permit development of new therapies.
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PMID:Endometrial Cancer and Hypermethylation: Regulation of DNA and MicroRNA by Epigenetics. 2254 75


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