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

PTEN is a newly isolated candidate tumor suppressor gene and its mutation is the most frequently found in endometrial cancer (EC), a very common female pelvic malignant disease. Mutations of the KRAS gene are also reported in this disease. Recent analysis of the PTEN protein suggested the possibility that this protein acts in the same pathway as does the RAS protein. To elucidate this possibility further, we performed a mutation analysis of these two genes in 44 endometrial cancer specimens (38 primary tumors and 6 cell lines). Altogether 23 (52%) of 44 tumors had mutations in either PTEN or KRAS, but none of them had mutations in both of these genes. These results support the idea that the protein products of these two genes act in the same growth regulatory pathway in the endometrium.
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PMID:Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer. 1076 69

Animals of the BDII inbred rat strain are known to be genetically predisposed to endometrial adenocarcinoma (EAC). Using them as models of human EACs, we studied tumors arising in F1 and F2 progeny from BDII animals crossed to animals from two other inbred strains, in which EACs were quite rare. In order to identify chromosomal regions exhibiting DNA copy number changes, comparative genomic hybridization (CGH) was applied in a series corresponding to 27 different solid tumors, most of which were classified as EACs, from these animals. The main findings from the study were that, although many different chromosomes were involved in copy number variation, some of the changes detected were recurrent and quite specific. Among specific changes found were gains in rat chromosome (RNO) regions 4q12 approximately q22, 6q14 approximately q16, and whole chromosome arms in some of the small metacentric chromosomes (e.g., RNO14, 16, and 18). RNO10 was involved in gain in the terminal and proximal regions. Each of these regions contains previously identified cancer-related genes representing possible candidates to be involved in the development of EAC. Furthermore, it was observed that there were clear differences in the pattern of copy number changes between tumors occurring in the two different crosses, and also between solid tumors and cell cultures. Endometrial cancer is the most common human gynecological cancer, but not much is known about specific genetic changes influencing this disease. Two genetic alterations that have been reported from human endometrial cancer are amplification of the ERBB2 gene and mutations in the 12 codon of the KRAS gene. One case of Erbb2 amplification was found but there were no Kras mutations in the rat material studied. We conclude that molecular genetic analysis of the rat BDII model will provide important new information about EAC in mammals.
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PMID:Analysis of genetic changes in rat endometrial carcinomas by means of comparative genomic hybridization. 1142 50

Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.
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PMID:Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. 1627 42

Both hypermethylation of the tumor suppressor gene RASSF1A and activating mutations of the KRAS and/or BRAF gene have been reported in a variety of human cancers. To investigate these epigenetic and genetic alterations in endometrial carcinoma (EC), we examined their frequency in 4 uterine EC cell lines and in 75 sporadic primary ECs. Using methylation specific PCR, we found RASSF1A methylation in 25 of 75 (33.3%) ECs. RASSF1A methylation was significantly associated with microsatellite instability (MSI, p < 0.001) and also with hMLH1 methylation (p < 0.001). KRAS mutations were detected in 14 of 75 (18.7%) ECs. BRAF mutations were identified in only 3 of 75 (4.0%) ECs and were not found in ECs with KRAS mutations or RASSF1A methylation. RASSF1A methylation was more frequent in KRAS mutation-negative ECs than in KRAS mutation-positive ECs (37.7% vs 14.3%), but this inverse correlation is not statistically significant (p = 0.122). However, we observed that RASSF1A methylation was inversely correlated with KRAS and/or BRAF mutations (p = 0.028) in MSI-negative ECs, while this inverse correlation disappeared in MSI-positive ECs. Furthermore, in MSI-positive ECs, 2 cases of concomitant RASSF1A methylation and KRAS mutation were found. Taken together, these results provide strong evidence that, in EC tumorigenesis, RASSF1A promoter hypermethylation is as important as KRAS mutations in activating the RAS pathway.
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PMID:RASSF1A hypermethylation and its inverse correlation with BRAF and/or KRAS mutations in MSI-associated endometrial carcinoma. 1661 51

The extracellular-regulated kinase (ERK) signaling pathway plays important roles in regulating the malignant potential of cancer cells in vitro. However, the effect of ERK signaling on the prognosis of human tumors is not clearly understood. The present study examined the expression of phosphorylated ERK1/2 (p-ERK1/2) as a hallmark of ERK activation, in relation to KRAS and BRAF mutations, in 63 endometrial cancer specimens with endometrioid-subtype, in order to clarify the prognostic value of p-ERK1/2 expression. Immmunohistochemical analysis revealed that 40 tumors (63%) expressed p-ERK1/2, with varying levels of expression. Total ERK1/2 expression was also evaluated in a subset of tumors; most cases expressed ERK1/2 constitutively but no correlation was observed with p-ERK expression, indicating that p-ERK1/2 staining was not due to ERK overexpression but to hyperactivation of ERK1/2. There was no statistically significant correlation between p-ERK1/2 expression and clinicopathological features, including patient age, International Federation of Gynecology and Obstetrics stage, pathological grade, myometrial invasion and lymph node metastasis. Sequencing analysis indicated that 23% of patients had a mutation in exon 1 of KRAS, whereas none of the patients had a mutation in exons 11 or 15 of BRAF, which are reportedly hot spots for mutation in many tumor types. There was no significant correlation between KRAS or BRAF status and p-ERK1/2 expression. Unexpectedly, patients with low p-ERK1/2 expression had significantly lower relapse-free survival (P = 0.041) and overall survival (P = 0.020). Multivariate Cox regression analysis indicated that p-ERK1/2 expression was an independent prognostic indicator for overall survival (P = 0.047). These findings suggest that ERK activation occurs in a KRAS- and BRAF-independent manner in endometrial cancer, and is associated with favorable prognosis.
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PMID:Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis. 1738 89

While the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is known to be activated in multiple sporadic cancers, the role of this pathway in familial tumors is mostly unknown. We searched for alterations in the catalytic domain of PI3K (PIK3CA), PTEN and KRAS, all of which may contribute to PI3K/AKT pathway activation, in a total of 160-familial colorectal (CRC) and endometrial carcinomas (EC), stratified by the presence vs. absence of germline mutations in DNA mismatch repair (MMR) genes. PIK3CA alterations (consisting of point mutations or low-level amplification, which were mutually exclusive with 1 exception) occurred in 10/70 (14%) of CRCs and 19/90 (21%) of ECs. Within ECs, amplification was significantly associated with the subgroup lacking germline mutations in MMR genes (familial site-specific endometrial cancer) (p = 0.015). Decreased or lost PTEN expression was characteristic of endometrial tumourigenesis (51/81, 63%, in EC compared with 24/62, 39%, in CRC, p = 0.004) and KRAS mutations of colorectal tumourigenesis (19/70, 27% in CRC vs. 9/89, 10%, in EC, p = 0.006) regardless of the MMR gene mutation status. PIK3CA alterations frequently coexisted with PTEN or KRAS changes. Combined with published studies on sporadic tumors, our data broaden the understanding of the role for PI3K pathway genes in human tumorigenesis.
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PMID:Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. 1747 59

In endometrial carcinomas (ECs), previous report suggested that PIK3CA mutations do not coexist with KRAS mutations, but the significant mutual exclusiveness has not been demonstrated. In this study, we examined the mutation frequency of PIK3CA in EC and its mutual exclusiveness with KRAS mutation. We performed mutational analysis of PIK3CA through a polymerase chain reaction single-strand conformation polymorphism assay in 44 cases of endometrial cancer and analyzed the correlation with loss of PTEN, KRAS mutation, and RASSF1A hypermethylation. Somatic mutations of PIK3CA were detected in 14 of 44 (31.8%) of endometrial cancers. In exon 9, seven PIK3CA mutations were located, while seven mutations were located in exon 20. The most common mutation was E545A (35.7%), followed by H1047R (28.6%). Concomitant loss of PTEN expression and PIK3CA mutation was found in four cases of endometrial cancer. KRAS mutations were mutually exclusive with PIK3CA mutations, and those mutations were inversely correlated with statistical significance (P = 0.039). Also, we found that mutations in ERBB2 were mutually exclusive with PIK3CA mutations. RASSF1A and hMLH1 methylation were not correlated with the presence of PIK3CA mutations. PIK3CA was frequently mutated in endometrial cancers. KRAS and PIK3CA mutations are inversely correlated, suggesting that genetic alterations of KRAS and PIK3CA may play equivalent roles in endometrial carcinogenesis.
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PMID:Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma. 1822 84

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.
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PMID:Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. 1875 3

MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for PTEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis.
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PMID:Endometrial cancer and somatic G>T KRAS transversion in patients with constitutional MUTYH biallelic mutations. 1898 Aug

Although molecularly targeted therapies have been effective in some cancer types, no targeted therapy is approved for use in endometrial cancer. The recent identification of activating mutations in fibroblast growth factor receptor 2 (FGFR2) in endometrial tumors has generated a new avenue for the development of targeted therapeutic agents. The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that cause craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation. Mutations that predominantly occur in the endometrioid subtype of endometrial cancer, are mutually exclusive with KRAS mutation, but occur in the presence of PTEN abrogation. In vitro studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074. Several agents with activity against FGFRs are currently in clinical trials. Investigation of these agents in endometrial cancer patients with activating FGFR2 mutations is warranted.
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PMID:FGFR2 as a molecular target in endometrial cancer. 1924 95


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