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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 (HNPCC), also called Lynch syndrome, is an autosomal dominantly inherited disorder of cancer susceptibility. Patients with HNPCC exhibit an increased risk for HNPCC-associated extracolonic tumors such as cancer of the endometrium. HNPCC is associated with germline mutations in DNA mismatch repair (MMR) genes: hMLH1, hMSH2 and hMSH6. Here, we describe two Japanese kindreds (0.5%) who met the new clinical criteria for HNPCC, Amsterdam criteria II, from among 375 endometrial cancer patients treated at Keio University Hospital from 1990 to 2002. From these results, it was found that female HNPCC patients comprised approximately 0.5% of all endometrial cancer patients. Decreased expression of two MMR gene protein products (hMLH1 and hMSH6) was confirmed immunohistochemically in these two endometrial tumors in HNPCC kindreds. This case report provides important information on Japanese HNPCC patients occurring endometrial cancer.
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PMID:Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria II. 1523 4

Previous studies from our laboratory indicated that expression of the MLH1 DNA mismatch repair (MMR) gene was necessary to restore cytotoxicity and an efficient G(2) arrest in HCT116 human colon cancer cells, as well as Mlh1(-/-) murine embryonic fibroblasts, after treatment with 5-fluoro-2'-deoxyuridine (FdUrd). Here, we show that an identical phenomenon occurred when expression of MSH2, the other major MMR gene, was restored in HEC59 human endometrial carcinoma cells or was present in adenovirus E1A-immortalized Msh2(+/+) (compared with isogenic Msh2(-/-)) murine embryonic stem cells. Because MMR status had little effect on cellular responses (i.e. G(2) arrest and lethality) to the thymidylate synthase inhibitor, Tomudex, and a greater level of [(3)H]FdUrd incorporation into DNA was found in MMR-deficient cells, we concluded that the differential FdUrd cytotoxicity between MMR-competent and MMR-deficient cells was mediated at the level of DNA incorporation. Analyses of ATPase activation suggested that the hMSH2-hMSH6 heterodimer only recognized FdUrd moieties (as the base 5-fluorouracil (FU) in DNA) when mispaired with guanine, but not paired with adenine. Furthermore, analyses of incorporated FdUrd using methyl-CpG-binding domain 4 glycosylase indicated that there was more misincorporated FU:Gua in the DNA of MMR-deficient HCT116 cells. Our data provide the first demonstration that MMR specifically detects FU:Gua (in the first round of DNA replication), signaling a sustained G(2) arrest and lethality.
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PMID:DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. 1561 Oct 52

The breast, ovary and endometrial cancers are hereditary in 5 to 10% of the cases. These genetic predisposition syndromes can be classified into two major classes: ovarian cancer and breast cancer predisposition family cases (genes BRCA1 and BRCA2) and family cases of colon cancer, endometrial cancer and ovarian cancer (Lynch syndrome or HNPCC) (genes hMLH1, hMSH2, hMLH6). The estimate of the family and individual risk can contribute in a determining manner to the management of these patients, by the practice of screening or an adapted prevention. Indeed, the risk of cancer of an individual having a positive test for a gene of predisposition to breast cancer (BRCA1, BRCA2) or to the colon cancer (hMLH1, hMSH2, hMLH6) lies between 50 and 70% at the age of 70 years. The indication of a genetic test must be discussed within the framework of an oncogenetic consultation. An individual and family medical management ranging from simple monitoring to prophylactic surgery is proposed to these predisposed people.
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PMID:[Hereditary predispositions to gynaecological cancers]. 1663 Jul 43

Impaired mismatch repair (MMR) is reportedly crucial in the early stages of endometrial carcinogenesis. Although estrogen exposure is considered an important risk factor for endometrial carcinoma, the relationship between estrogen and MMR activity remains undetermined. The present study was undertaken to elucidate the effect of estrogen on MMR activity in normal and malignant endometrial cells. The expression of MMR proteins, hMLH1 and hMSH2, and its correlation with estrogen was examined using immunohistochemical and immunofluorescent techniques. The effect of estradiol (E2) on the expression of hMLH1/hMSH2 protein/mRNA and in vitro MMR activity using two types of heteroduplex (G/T mismatches, 2-base insertion-deletion loops) was examined in cultured normal endometrial glandular cells and estrogen receptor-positive endometrial carcinoma Ishikawa cells. Immunohistochemical expression of hMLH1 and hMSH2 in normal endometrial glands was positively correlated with the serum E2 levels. The expression of hMLH1/hMSH2 protein and mRNA was increased in normal endometrial glandular and Ishikawa cells by E2 treatment. In vitro MMR activity was up-regulated by E2 in both types of cell and heteroduplex. Immunofluorescent analysis demonstrated that E2 enhanced proliferation and hMLH1/hMSH2 expression in both cells; however, proliferating cells without hMLH1/hMSH2 expressions implying high-risk cells were more frequently observed under low E2 concentrations. Collectively, the E2-induced up-regulation of MMR activity in endometrial cells suggests that high estrogen levels act as an intrinsic defense against endometrial carcinogenesis, whereas the imbalance between cell growth and MMR under low E2 environment as seen at postmenopause is vulnerable to carcinogenesis.
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PMID:Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells. 1682 17

Women in hereditary nonpolyposis colorectal cancer (HNPCC) families have up to a 71% lifetime risk for developing endometrial cancer (EC). This compares to the female lifetime risk for colorectal cancer (CRC) in HNPCC of 60%. The basis of HNPCC is an inherited mutation in a mismatch repair gene (MMR). Aspirin and COX2 inhibitors seem to have a chemoprotective effect on CRC in the general population and are the subject of prospective clinical studies in patients at high risk for CRC including HNPCC. There is no evidence that these agents have any protective effect against EC in the general population. This study investigated the effect of aspirin and a COX2 inhibitor (rofecoxib) on an HNPCC EC cell line model (Ishikawa) by assessing the effect on proliferation, apoptosis, the cell cycle, and MMR gene expression. Aspirin inhibits EC cell proliferation by inducing apoptosis and changes in the cell cycle. This effect is not mediated by changes in MMR gene (hMSH2) expression as assessed by quantitative reverse transcription-polymerase chain reaction. Rofecoxib inhibits EC cell proliferation; this did not appear to be mediated by induction of apoptosis, by alterations of the cell cycle, or by changes in MMR gene expression.
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PMID:Exploring the potential chemopreventative effect of aspirin and rofecoxib on hereditary nonpolyposis colorectal cancer-like endometrial cancer cells in vitro through mechanisms involving apoptosis, the cell cycle, and mismatch repair gene expression. 1731 60

Recently, a high rate of endometrial cancer has been reported in women with hereditary non-polyposis colorectal cancer (HNPCC), suggesting a relationship between familial endometrial cancers and HNPCC. Familial endometrial cancers constitute only about 0.5% of all endometrial carcinomas and it is essential to examine family histories in detail. A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC-associated endometrial cancers was performed. Mutations were detected in 18 of the 120 patients (15.0%). Most HNPCC-related endometrial cancers do not meet the New Amsterdam Criteria for HNPCC. These clinical criteria may identify only some HNPCC-associated endometrial cancers. Establishing the correct family history for endometrial cancer patients is important for diagnosing familial endometrial carcinomas. An analysis of MMR genes may be useful for patients with endometrial cancer showing familial aggregation. In addition, gynecologists must be accurately informed, and it is important to perform large-scale, multicenter studies both nationwide and internationally.
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PMID:Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer. 1862 96

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

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


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