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

HPV (types 16 and 18) DNA sequences are present in the majority of precancerous and cancerous lesions of the human uterine cervix. However, data concerning the involvement of HPVs infection in the pathogenesis of endometrial cancer are controversial. In the current study we investigated the frequency of the HPV types 16 and 18, detected by PCR amplification using the type 16- and 18-specific primers within the E7 Open Reading Frame (ORF) sequence, in 54 human endometrial carcinomas obtained from women of Polish origin. Moreover, we assessed the possible association of the HPV with the clinicopathological features of the cancer, patients' outcome as well as with the K-ras codon 12 gene point mutations. HPV type 16 was present in eleven out of 54 (20%) endometrial tumors, while HPV type 18 was detected only in three out of 54 (4%) neoplasms analyzed. HPV infection was not related either to the patients' age (r=0.11; p=0.428, Spearman correlation test) or to the clinicopathological parameters and patients' prognosis. A higher incidence of HPV 16/18 was detected in well (G1) differentiated than in moderately (G2) and poorly (G3) differentiated endometrial adenocarcinomas, but the difference was not statistically significant. Moreover, none of HPV-positive endometrial carcinomas harbored K-ras codon 12 gene point mutations. Our results suggest that some of the endometrial carcinomas are associated with HPV infection but the presence of the human papillamovirus types 16/18 is not related to the clinicopathological or prognostical features of the neoplasm.
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PMID:Detection of human papillomavirus types 16 and 18 in human neoplastic endometrium: lack of correlation with established prognostic factors. 1085 68

In the present study, we screened for the K-ras exon 2 point mutations in a group of 87 gynecological neoplasms (82 endometrial carcinomas, four carcinomas of the uterine cervix and one uterine carcinosarcoma) using the non-isotopic PCR-SSCP-direct sequencing techniques. Direct sequencing analysis revealed CAA-->CAC (Gln-->His) K-ras codon 61 point mutations in two (2.4%) of the 82 endometrial carcinomas mentioned above. These two cases were endometrial endometrioid carcinomas at an early clinical stage of disease (stage IB and IC due to FIGO). Those endometrial carcinomas that showed K-ras exon 2 point mutations revealed a strong positivity for heterogeneous nuclear retinoblastoma protein staining; none of these, however, have had the K-ras codon 12 point mutation. In addition, there were no K-ras gene point mutations in three endometrial carcinomas lacking the Rb protein immunohistochemically. None of the cervical carcinomas tested had K-ras gene point mutations, whereas one carcinosarcoma harbored K-ras codon 61 point mutation (CAA-->CAC). In conclusion, our data support the view that K-ras exon 2 point mutations are rare events in human endometrial cancer. Rb and K-ras gene abnormalities may occur independently of each other during endometrial carcinogenesis in humans.
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PMID:K-ras exon 2 point mutations in human endometrial cancer. 1117 36

To test the prognostic utility of MIB-1 in human endometrial neoplasias, the proliferative activities of fifty-two endometrial carcinomas obtained from Polish women were assessed. We also investigated the relationship between the MIB-1 Proliferative Index and the well-known clinicopathological features of cancer (clinical stage, histological type, histological grade, depth of myometrial invasion), patient's age, overall survival, retinoblastoma immunostaining and K-ras codon 12 point mutations. The mean MIB-1 Proliferation Index was 43.8%, with a median of 36.0%. Due to the great intratumour heterogeneity of the immunoreaction, the Index ranged from 0% to 98%. A significant relationship was noted between MIB-1 expression and histological grading (p = 0.0004) and myometrial invasion of cancer (p = 0.01). Multivariate Cox regression demonstrated that the clinical stage was the only independent prognostic factor during follow-up (p = 0.025). There was a tendency towards a poorer outcome for women with a Proliferative Index of > 31% than for patients whose Index was < or = 31%; the difference, however, did not reach significance (p = 0.25; log-rank test). Interestingly, uterine cancers lacking retinoblastoma protein expression had a mean MIB-1 Proliferation Index that was nearly twice as high as in those neoplasias that stained positively for retinoblastoma (70.33% and 42.14%, respectively; p = 0.09; Mann-Whitney-U test). There were no significant differences between K-ras codon 12 point mutation-positive and -negative endometrial carcinomas regarding the proliferative activity of the cancer (mean Indexes 47.6% and 43.8%, respectively; p = 0.66, Mann-Whitney-U test). Our data support the view that MIB-1 proliferative activity was significantly increased with a decrease of the histological grading and with the myometrial invasion of human endometrial cancer.
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PMID:Immunohistochemical analysis of MIB-1 proliferative activity in human endometrial cancer. Correlation with clinicopathological parameters, patient outcome, retinoblastoma immunoreactivity and K-ras codon 12 point mutations. 1155 Aug

Sporadic endometrial carcinoma can be divided into two biologically and clinically distinctive subtypes of which one is estrogen-related (type I), the other estrogen-unrelated (type II). Type I carcinomas occur at younger age, express estrogen (ER) and progesterone receptors (PR), are frequently associated with endometrial hyperplasia and show a good prognosis. Type II carcinomas occur at older age, are negative for ER and PR, arise in the background of atrophic endometrium and show poor prognosis. Histologically, endometrioid carcinomas correspond to type I carcinomas whereas serous carcinoma is the prototype of type II carcinomas. Endometrioid and serous carcinomas are significantly different with respect to their molecular changes. Endometrioid carcinomas frequently show microsatellite instability (MIN), PTEN and K-ras mutation but infrequently p53 mutations, loss of p16 expression and her2/neu amplification, respectively. In contrast, serous carcinomas show a high frequency of p53 mutations and often loss of p16 expression whereas MIN and PTEN and K-ras mutations are uncommon. Familial endometrial carcinoma associated with HNPCC occur about two decades earlier than sporadic carcinomas, show endometrioid histology and are frequently MIN positiv due to germline mutations of mismatch repair genes (mostly MLH1 and MSH2). During the progression of endometrioid carcinoma PTEN mutations and MIN are considered early changes since they are present in a high frequency in atypical endometrial hyperplasia whereas p53 mutations, loss of p16 expression and her2/neu amplification are considered late events since they are predominantly found in poorly differentiated tumors. In contrast, p53 mutations are considered an early event in the pathogenesis of serous carcinoma occurring already in its putative precursor endometrial intraepithelial carcinoma (EIC). The future research will focus, besides the discovery of new relevant genes, on the interaction of known genes as well as their clinical relevance.
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PMID:[Dualistic model of molecular pathogenesis in endometrial carcinoma]. 1187 8

Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. Histologically, endometrioid and mucinous carcinomas are considered type I, serous and clear cell carcinomas type II. Molecular data from multiple studies support the hypothesis of different genetic pathways in the development of endometrioid and serous carcinoma. The most frequent genetic alteration in endometrioid carcinoma is PTEN inactivation by mutation, followed by microsatellite instability (MIN) and mutations of K-ras and beta-catenin. PTEN and K-ras mutations and MIN are considered early events, occurring in a subset of atypical endometrial hyperplasia, whereas p53 mutation is considered a late event, during progression of about 10-20% of endometrioid carcinomas. In serous carcinoma, p53 mutation is the most frequent genetic alteration, followed by inactivation of p16 and e-cadherin and amplification of her2/neu. p53 mutation occurs in endometrial intraepithelial carcinoma, the putative precursor of serous carcinoma. Considering these genetic pathways, the current histological classification of endometrial carcinoma is molecular based.
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PMID:Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification. 1474 44

A considerable amount of evidence indicates that Ras signaling contributes to the development of endometrial cancer. We previously demonstrated that endometrial cancer cells carrying oncogenic [(12)Val]K-ras were susceptible to apoptosis. The present study examined the role of K-and H-Ras in the induction of apoptosis using rat endometrial cells (RENT4 cells). We found that constitutively activated K-Ras promoted apoptotic cell death, whereas the H-Ras mutant rescued rat endometrial cells from apoptosis. Expression of a constitutively active form of Raf-1 (Raf-CAAX) promoted apoptosis, whereas expression of a constitutively active catalytic subunit of phosphoinositide 3-kinase, p110K227E, allowed cells to escape from apoptosis. Moreover, inhibition of the MEK-MAPK pathway by the specific inhibitor, UO126, rescued the cells from apoptosis, whereas the inhibition of phosphoinositide 3-kinase by its specific inhibitor, LY294002, promoted apoptosis in RENT4 cells expressing activated K-Ras. However, both inhibitors promoted apoptosis in RENT4 cells expressing activated H-Ras. This difference in the regulation of apoptosis by the MEK inhibitor between K-Ras- and H-Ras-expressing cells depended on the interaction of effector proteins downstream of each Ras isoform. Finally, to elucidate the role of downstream K-Ras signal pathways, we generated K-Ras effector domain mutants (K12V35S, K12V40C). We examined the incidence of apoptotic cell death induced by the K-Ras effector domain mutants (K12V35S, K12V40C). The relative ratio of phospho-MAPK to phospho-Akt compared with that of mock cells was higher in K12V35S cells than in K12V40C cells. Ectopic expression of K12V35S protein increased the proportion of apoptotic cells, and in turn, the expression of K12V40C protein decreased compared with the expression of K12V protein without the effector domain mutant. These results demonstrate that K- and H-Ras-mediated signaling pathways exert distinct effects on apoptosis and that K-Ras downstream Raf/MEK/MAPK pathway is required for the induction of apoptosis in endometrial cells. Coordination of the two pathways contributes to endometrial cell survival.
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PMID:K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival. 1508 91

Several pathways have been implicated in the pathogenesis of endometrial carcinoma. Based on recent reports, BRAF mutations provide an alternative route for activation of the RAS signalling pathway. The CDKN2A (p16) tumour suppressor gene is also altered in several tumour types. We therefore wanted to assess the pattern and prognostic impact of BRAF mutations and p16 alterations in endometrial carcinomas. Only 1 of 48 tumours (2%) was found to have a BRAF mutation in exon 15, whereas 8 of 45 tumours (18%) had a K-ras mutation. Homozygous deletion, amplification, promoter region methylation or mutation of the p16 gene was seen in 6 cases (13%), and 18 cases (38%) carried polymorphisms in the p16 gene. All tumours with presence of p16 methylation, non-sense mutation, deletion or amplification exhibited loss of p16 expression as evaluated by immunohistochemistry. Presence of a p16 hit was significantly correlated with high FIGO stage (p = 0.04), high histologic grade (p = 0.02), estrogen receptor negativity (p = 0.05), pathologic expression of p53 (p = 0.02), pathologic expression of p16 (p = 0.05) and poor survival (p = 0.02). There was also a significant correlation between loss of p16 expression and K-ras mutations, pathologic p53 expression and serous papillary/clear cell histologic types (p = 0.05/p = 0.001/p = 0.002). In conclusion, BRAF mutation is an infrequent finding in endometrial carcinomas. Loss of p16 expression is seen in all cases with alterations of the p16 gene. The presence of a p16 hit might be important in a subset of endometrial carcinomas with aggressive clinical behaviour. However, the mechanism of p16 inactivation remains unclear for the majority of cases exhibiting loss of expression, but the interactions with K-ras and p53 should be further studied.
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PMID:Low frequency of BRAF and CDKN2A mutations in endometrial cancer. 1572 90

Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia. In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease. In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.
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PMID:Distinct molecular alterations in complex endometrial hyperplasia (CEH) with and without immature squamous metaplasia (squamous morules). 1616 Apr 75

A dualistic model, which has been established on a morphological basis and that differentiates type I endometrioid from type II non-endometrioid endometrial cancer, is widely accepted. Molecular genetics have provided us with data supporting the dualistic model of endometrial tumorigenesis and with some clues to speculate about the sequence of the molecular alterations defining the tumorigenesis pathways. In type I endometrioid endometrial cancer, PTEN gene silencing, microsatellite instability associated with defects in DNA mismatch repair genes, or mutations in the K-ras gene are the known major alterations defining the progression from normal endometrium to hyperplasia and then on to carcinoma. Recently, cDNA microarray technology for identifying the differences in gene expression patterns between the histological types of endometrial cancer have permitted the identification of differentially expressed genes that could help us to understand differences in the biology and the clinical outcome between histiotypes. Genes involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, or altered genes associated with the initial steps of myometrial infiltration in endometrioid endometrial cancer, represent examples of how useful large genetic screenings can be for understanding the tumorigenesis process and the future directions in the molecular pathogenesis of endometrial cancer.
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PMID:Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors. 1632 44

Several genetic mutations have been identified in human endometrial cancers, but the specific combinations of mutations required to form endometrial cancer cells remain unknown. In the present study, we established an in vitro model of endometrial carcinogenesis, in which defined genetic elements were introduced into endometrial epithelial cells to create transformed endometrial cells at different stages. Introduction of the human papillomavirus type 16 E6/E7 gene and the human telomerase reverse transcriptase (hTERT) gene into human primary endometrial epithelial cells was sufficient to generate immortalized cells. Introduction of hTERT in early passages stabilized telomeres and created immortalized cells with normal karyotype, whereas introduction of hTERT in later passages generated immortalized cells but with widespread chromosome abnormalities. However, neither of those two immortalized cell lines exhibited tumorigenic phenotypes. Tumorigenic endometrial epithelial cells with invasive capacity were created by introducing a mutant K-ras allele into immortalized cells, keeping their chromosomes intact. Inhibiting the PTEN gene and activating Akt pathways did not create tumorigenic phenotypes, although the latter conferred anchorage-independent growth capacity. These findings suggest that neoplastic transformation of human endometrial cells can occur in the absence of widespread chromosomal abnormality, and that the combination of Rb inactivation, telomerase activation and altered K-ras signaling is sufficient for in vitro neoplastic transformation. The present experimental model can help clarify the genetic requirements for endometrial carcinogenesis, and it is useful for testing and developing specific inhibitors of specific oncogenic pathways.
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PMID:Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements. 1663 65


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