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

Microsatellite instability (MSI) is a characteristic feature of hereditary nonpolyposis colorectal cancer and is also observed in sporadic colorectal and endometrial cancers. Alterations in the mismatch repair genes hMLH1 and hMSH2 are important for the development of MSI. It has recently been demonstrated that hypermethylation of the hMLH1 promoter region is associated with MSI and appears to be a common mechanism for gene inactivation. For endometrial carcinoma, however, previous studies have been relatively small and have not been population based. We therefore wanted to assess the frequency and prognostic significance of hypermethylation of the hMLH1 and hMSH2 genes in conjunction with hMLH1 protein expression in a prospective and population-based series of endometrial carcinoma patients with known MSI status and complete follow-up. A total of 138 patients were studied, and methylation of hMLH1 was found in 23% of tumors with conclusive results, whereas methylation of hMSH2 was seen in only 1% of tumors. Methylation of hMLH1 was significantly correlated with MSI (P < 0.001). Loss of nuclear staining of hMLH1 protein was seen in 14% of the cases and was significantly correlated with hMLH1 methylation and MSI (P < 0.001). Normal expression of hMLH1 was seen in all of the unmethylated tumors (100%). Of the 14 MSI-positive tumors that were also methylated, all but 1 (93%) showed a loss of nuclear expression of hMLH1. None of the tumors with loss of hMLH1 expression or hMLH1 methylation were aneuploid (P for both < or = 0.05), and loss of hMLH1 expression and hMLH1 methylation was significantly correlated with lack of p53 overexpression (P for both < or = 0.05). Nuclear hMLH1 staining and hMLH1 methylation did not significantly influence survival. In conclusion, hMLH1 methylation was common and was significantly correlated with loss of hMLH1 protein expression, MSI, diploid tumors, and lack of p53 overexpression. In contrast, hMSH2 methylation was infrequent in this prospective and population-based series of endometrial carcinomas.
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PMID:Methylation of hMLH1 in a population-based series of endometrial carcinomas. 1099 52

Endometrial carcinoma is the most common gynecologic malignancy in perimenopausal and postmenopausal women. A role of mismatch repair genes, like hMLH1 and hMSH2 in their pathogenesis, has been suggested. Loss of their function leads to the accumulation of replication errors (mutator phenotype), which are responsible for further mutations in genes with microsatellite sequences in their coding region, such as Bax. We analyzed the expression of hMLH1, hMSH2, and Bax genes in 89 formalin-fixed paraffin-embedded endometrial carcinomas. The immunostains were scored with regard to percentage of positive tumor cells (0%, <10%, 10 to 50%, >50%), and relative staining intensity (1+, 2+, 3+). The staining results were correlated with clinicopathologic features and survival. Loss of hMSH2 expression (0% positive cells) was observed in 1.1% (1/89) of the tumors; loss of hMLH1 was seen in 12.4% (11/89) of the cases, particularly in endometrioid tumors with mucinous differentation (5/11; 45%; P =.03). No significant association was found between the immunoscores and grade, stage criteria of the International Federation of Obstetrics and Gynecology (FIGO), or age of the patients. Among 11 tumors with loss of Bax expression (12.4%), 4 had also loss of hMLH1 (4/11; 36.4%; P =.017). In multivariate analysis (Cox model), significantly longer survival was found for patients with tumors in FIGO Stage I-II (P <.0001), endometrioid type (P =.001), low grade (P =.001), and absence of hMLH1 expression (P =.027). Our results suggest that loss of function of hMLH1 and Bax occur in a subgroup of endometrial carcinoma. In addition to the classical prognostic factors, absence of hMLH1 expression is associated with better outcome of patients.
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PMID:Prognostic relevance of hMLH1, hMSH2, and BAX protein expression in endometrial carcinoma. 1150 37

Microsatellite instability (MSI) seems to be important in the development of various human cancers including sporadic endometrial cancer. It has previously been shown that alterations in the mismatch repair gene hMLH1 seem to be important for the development of MSI in these tumors. The role of the other mismatch repair genes hMSH2 and hMSH6 has been less well studied, but investigations on patients with hereditary nonpolyposis colorectal cancer indicate that these genes also may be involved. We therefore wanted to investigate the pattern of hMSH2 and hMSH6 expression in a prospective and population-based series of endometrial carcinomas with known hMLH1 expression and MSI status. A total of 138 patients were studied, and pathological staining was seen in 19 cases (14%) for hMLH1, 26 cases (19%) for hMSH2, and 17 cases (12.3%) for hMSH6. Pathological hMLH1 expression was more frequent among tumors with high MSI (those positive for four to five of five markers), whereas pathological expression of hMSH2 and hMSH6 was more frequent among tumors with intermediate MSI (those positive for two to three of five markers). MSI was significantly correlated with pathological expression of hMLH1 (P < 0.001), hMSH2 (P = 0.04), and hMSH6 (P = 0.001). In the group with high MSI, 14 of 16 tumors (88%) showed pathological expression for at least one of the markers. The expression of hMLH1, hMSH2, or hMSH6 did not significantly influence survival. In conclusion, pathological expression of hMLH1 does not seem to account for all tumors with a MSI-positive phenotype in this population-based series of endometrial carcinomas. Our data indicate that the other mismatch repair genes hMSH2 and hMSH6 are also involved, especially in cases with intermediate MSI.
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PMID:Loss of hMSH2 and hMSH6 expression is frequent in sporadic endometrial carcinomas with microsatellite instability: a population-based study. 1180 50

Microsatellite instability (MSI) due to replication errors occurs frequently in hereditary tumors. Association with functional inactivation of the mismatch repair (MMR) genes and lack of protein expression has been described. In endometrial carcinoma (EC), the prevalence and clinical significance of these phenomena are not well known. Therefore, DNA samples from 89 EC and 5 metachronous tumors were analyzed with polymerase chain reaction, using 5 microsatellite markers and a DNA sequencer for amplicon detection. The results were correlated with immunohistochemistry of hMLH1 and hMSH2. MSI at >or=2 loci (MSI-H) was detected in 10/89 EC (11%); 1 of 10 showed loss of both hMLH1 and hMSH2, and 5 of 10 showed loss of hMLH1 (P < 0.0001). MSI-H was observed frequently in tumors with mucinous differentiation (P = 0.048), >10% of solid-cribriform pattern (P = 0.037), International Federation of Obstetrics and Gynecology (FIGO) stage III to IV (4 of 13; P = 0.016), and necrosis >5% (P = 0.07). Loss of heterozygosity (LOH) in >or=1 loci was found in 17 of 156 (11%). Survival (Kaplan-Meier) was longer for patients with endometrioid tumors with predominant glandular pattern, <5% necrosis, low FIGO stage and grade, superficial myometrial infiltration, no lymph-vascular invasion (LVI), and loss of hMLH1 expression (all P <or= 0.04). Cox analysis showed independent value for stage, grade, histologic type and pattern, LVI, and hMLH1 expression (all P < 0.05). Age, MSI status, LOH, peritumoral inflammatory reaction, hMSH2, and development of metachronous tumors did not influence survival. In conclusion, MSI phenotype was observed in a small subset of mainly advanced-stage EC, frequently showing mucinous differentiation, areas of solid-cribriform pattern, and necrosis. It is often associated with loss of hMLH1 expression, which may be a prognostic marker, but only rarely with defects of hMSH2.
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PMID:Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma. 1197 77

Effectiveness of radiotherapy is influenced by several genetic properties of the targeted cells. The aim of this study was the identification of prognostic indicators of tumor response to radiation in cervical and endometrial cancer. Using microsatellite DNA analysis, we investigated 31 markers, located on 1p, 2p, 2q, 3p, 9p, 9q, 13q, 17p and 17q for genomic alterations in 37 cervical and 21 endometrial cancer cases, with complete follow-up data. Genetic alterations of the initial tumor genotypes were observed after radiation in 86.5% of cervical and 81.0% of endometrial cases. Reversions to the original normal genotype were observed in 40.5 and 28.6% respectively, predominantly in cured patients rather than in recurred cases. Survival curves by the Kaplan-Meier method showed a worse prognosis for cervical cancer patients whose tumors harbor allelic imbalance (AI) on 3p or 13q, and for endometrial cancer patients whose tumors harbor AI on 13q. Our data suggest a possible association of the hMLH1 or BRCA2 genes, implicated in distinct DNA repair pathways and located on 3p and 13q respectively, with response of cervical and endometrial cancer to radiotherapy. Moreover, microsatellite DNA analysis before and after radiation treatment could be used as a marker of the clinical outcome of patients.
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PMID:Allelic imbalance in hMLH1 or BRCA2 loci associated with response of cervical and endometrial cancer to radiotherapy. 1206 Aug 51

Microsatellite instability (MSI) is detected in about 20-25% of endometrial cancers (ECs). Incidence of this alteration correlates with lack of expression of certain mismatch repair genes such as hMLH1 and hMSH2. Although assessment of several markers has been proposed for identification of microsatellite unstable tumours, BAT-26, a mononucleotide microsatellite repeat, has been shown to be highly efficient when used as a single marker. The aim of the study was to evaluate instability within BAT-26 and expression of hMLH1 and hMSH2 proteins in sporadic endometrial cancer as well as to correlate these findings with histopathologic and clinical characteristics of tumours. Samples of 88 (74 endometrioid and 14 non-endometrioid) ECs were investigated for instability within BAT-26 by means of PCR and expression of hMLH1 and hMSH2 proteins using immunohistochemistry. BAT-26 MIS was discovered in 23.9% of endometrial cancers. Incidence of MSI did not correlated with grade, stage or depth of invasion. BAT-26 MSI was more frequent in non-endometrioid compared to endometrioid tumours (35.7% vs. 21.6%, respectively), but the difference was not statistically significant. Lack of hMLH1 and hMSH2 protein expression was detected in 21.6 and 15.9% of ECs, respectively, and did not correlate with clinicopathologic features of tumours. Loss of both hMLH1 and hMSH2 protein expression was similar in BAT-26 stable and unstable cancers. All cases of non-endometrioid tumours with BAT-26 MSI were positive for hMLH1. We can conclude that BAT-26 used alone may not be a reliable marker for identification of sporadic ECs with microsatellite instability induced by deficient expression of hMLH1 and hMSH2.
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PMID:BAT-26 microsatellite instability does not correlate with the loss of hMLH1 and hMSH2 protein expression in sporadic endometrial cancers. 1279 67

Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.
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PMID:Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation? 1457 6

Alterations in the mismatch repair genes (hMLH1 and hMSH2) play an important role in the development of microsatellite instability in sporadic endometrial cancer. Tissue microarray technology allows molecular profiling of tumor samples at the DNA, RNA, and protein levels. We analyzed hMLH1 and hMSH2 expression by immunohistochemistry in a group of atypical endometrial hyperplasias (n = 10), endometrioid endometrial carcinomas (n = 58), and nonendometrioid endometrial carcinomas (n = 27) on tissue microarray. The results were correlated with microsatellite instability status as evaluated by BAT-25 and BAT-26. Overall, 29.4% of lesions showed microsatellite instability. Loss of nuclear hMLH1 and hMSH2 protein expression was seen in 22.3% and 6.5% of cases, respectively. Immunohistochemistry for hMLH1 and hMSH2 showed lack of protein expression in 64% and 16.6% of microsatellite instability-positive endometrial lesions, respectively. Taken together, hMLH1 or hMSH2 protein expression was absent in 18 of 24 microsatellite instability-positive cases (75% sensitivity). A high level of concordance was found between immunohistochemistry for hMLH1 and hMSH2 and microsatellite instability status evaluated by BAT-25 and BAT-26 (kappa value of 0.7). Of the 57 cases found to be microsatellite instability negative, 53 showed normal expression of both proteins (93% specificity). The observed predictive value of absence of expression of hMLH1 for predicting microsatellite instability-positive status was 82%. The predictive value of normal expression of both proteins for predicting microsatellite instability-negative status was 90%. These results are consistent with those previously reported in whole tissue sections. Therefore, immunohistochemical analysis of hMLH1 and hMSH2 expression on tissue microarray provides an accurate technique for screening for tumors with microsatellite instability. Tissue microarrays represent an ideal approach for comparing different diagnostic or predictive markers with one another in consecutive tissue microarray sections.
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PMID:Tissue microarray immunohistochemical expression analysis of mismatch repair (hMLH1 and hMSH2 genes) in endometrial carcinoma and atypical endometrial hyperplasia: relationship with microsatellite instability. 1461 55

Women predisposed to hereditary nonpolyposis colorectal cancer are at high risk of developing endometrial carcinoma at a young age. Hereditary nonpolyposis colorectal cancer-associated endometrial carcinomas are of the endometrioid type, usually arise from complex atypical hyperplasia, and often show microsatellite instability. To identify occult hereditary nonpolyposis colorectal cancer individuals among endometrial carcinoma patients, we examined complex atypical hyperplasias and endometrial carcinomas of 60 women < or =50 years of age (mean age: 35.7 years) using microsatellite instability, immunohistochemistry, and DNA sequence analysis. Three patient groups were recruited: group 1, patients with complex atypical hyperplasia exclusively (n = 27); group 2, patients with complex atypical hyperplasia and synchronous or metachronous endometrial carcinoma (n = 15); group 3, patients with endometrial carcinoma only (n = 18). Overall, 13 of 33 endometrial carcinomas (39%) displayed high-level microsatellite instability. None of the complex atypical hyperplasias in group 1 had high-level microsatellite instability or loss of hMLH1/hMSH2 protein expression. In group 2 patients, 33% of complex atypical hyperplasias and 53% of endometrial carcinomas had high-level microsatellite instability. Loss of hMSH2 protein expression was found in six endometrial carcinoma patients, five of them with verified hMSH2 germline mutations, including four patients with high-level microsatellite instability in complex atypical hyperplasia. Among group 3 patients, 28% of endometrial carcinomas displayed high-level microsatellite instability; three of those five endometrial carcinomas were from patients with multiple extrauterine hereditary nonpolyposis colorectal cancer-associated tumors. We conclude that young women (< or =50 years of age) with concurrent complex atypical hyperplasia and multiple hereditary nonpolyposis colorectal cancer-associated carcinomas are at risk of developing high-level microsatellite instability endometrial carcinoma. Combined microsatellite instability and immunohistochemistry analysis allows the identification of a high proportion of hereditary nonpolyposis colorectal cancer patients among young women with endometrial carcinoma and complex atypical hyperplasia. All complex atypical hyperplasias with high-level microsatellite instability progressed to endometrial carcinoma. Only one third of the complex atypical hyperplasias with microsatellite stability progressed to high-level microsatellite instability endometrial carcinoma, while seven complex atypical hyperplasias progressed to microsatellite stability endometrial carcinoma. Microsatellite analysis of complex atypical hyperplasia in young patients may therefore be a useful prognostic marker for predicting possible progression to high-level microsatellite instability endometrial carcinomas.
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PMID:Molecular analysis of endometrial hyperplasia in HNPCC-suspicious patients may predict progression to endometrial carcinoma. 1466 45

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


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