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

Tumorigenesis in humans and experimental animals appears to involve the activation of ras protooncogenes for a number of organ systems and seems to be important to the development of the metastatic phenotype in several model systems. Clinically, the presence of activated ras protooncogenes has been reported to be a negative prognostic factor in the myelodysplastic syndrome and in adenocarcinoma of the lung. In the present study we examined 49 cases of endometrial carcinoma for mutations in the first exon of K-ras using the polymerase chain reaction and direct sequencing. Mutations in codon 12 or 13 of K-ras were detected in 6 of 49 cases (12.2%). These six cases consisted of five endometrioid endometrial carcinomas, each of which had a mutation in codon 12, and one case of clear cell carcinoma, which had a mutation in codon 13. In our study the presence of mutations in K-ras appeared to be an unfavorable prognostic factor. Three of six patients with the mutation died during follow-up, while only 7% of the 43 patients without K-ras mutations expired during this same period. In multivariate analysis using the Cox proportional hazard model, K-ras activation appeared to be an independent risk factor when compared with clinical stage, depth of myometrial invasion, and patient age. Thus, our findings support the hypothesis that K-ras protooncogene activation plays an important role in determining the aggressiveness of endometrial carcinoma.
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PMID:Clinical implications of K-ras mutations in malignant epithelial tumors of the endometrium. 158 90

To study hormone responsive genes in differentiated epithelial cells and as a model for endometrial carcinoma, lines were established from primary rat endometrial cells by infection with replication-defective retroviruses carrying oncogenes and the selectable gene neo. The initial step involved immortalization through the large T antigen of SV40 to generate a line we designate RENT4, or with the E1a gene of adenovirus to generate lines referred to as RENE1 and RENE2. Additionally, lines generated by large T antigen of SV40 were superinfected with a replication-defective retrovirus harboring the v-Ha-ras oncogene and selected by the ability to form colonies in soft agar. The latter cell lines appeared fully transformed and were designated RENTR01 and RENTR03. Five established lines were characterized for steroid hormone receptors, alkaline phosphatase activity and their complement of the intermediate filaments vimentin and cytokeratin. With the exception of the RENE1 cells all other lines have normal levels of glucocorticoid receptor, whereas only RENE1, RENE2 and RENT4 were positive for the progesterone receptor. RENTR01, RENTR03 and, to a lesser extent, RENE1 exhibited differential expression of cytokeratins dependent upon whether the cells were grown on a substrata of NIH3T3 cells. When grown on formalin-fixed NIH3T3 cells, RENTR01 and RENTR03 cells appeared to differentiate or rearrange themselves in culture. Individual islands of cells showed a heterogeneous pattern of intermediate filaments with vimentin-positive cells localized to the outer portion of the islands whereas cytokeratin-positive cells are seen on the insides of these structures.
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PMID:Establishment of rat endometrial cell lines by retroviral mediated transfer of immortalizing and transforming oncogenes. 169 89

Protein carboxylmethyltransferases (PCMT), enzymes that methylate free carboxyl groups of proteins, are involved in functional modification of various proteins including those of age-damaged proteins and the oncogenic ras proteins. Several species of PCMT are associated with these modifications. By using western blot analysis and specific antibodies raised against one type of PCMT, a 30-kilodalton (KD) cytosolic enzyme from Torpedo electric organ was identified in human erythrocytes and endometrium. The high specificity of the antibodies made it possible to compare levels of immunoreactive 30-KD PCMT protein in normal human endometria and endometrial carcinomas. Assays done on samples from 23 patients indicated the average levels of immunoreactive 30-KD PCMT in endometrial carcinomas was one fifth that of normal endometrium. The sensitivity of the assay was 83%, and its specificity was 90%. These results suggest that levels and activity of the 30-KD PCMT may be downregulated to maintain the phenotypic expression of the endometrial carcinoma. These assays may be used to assist in the detection of endometrial carcinomas.
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PMID:Downregulation of specific protein carboxylmethyltransferase immunoreactivity in human endometrial carcinoma. 191 17

To understand the molecular mechanism of endometrial differentiation we have initiated an analysis of the uteroglobin promoter. Uteroglobin is normally expressed in endometrial tissues under the control of ovarian hormones. In gene transfer experiments with the Ishikawa cell line, derived from a human endometrial adenocarcinoma, we have identified several regions in the promoter of the uteroglobin gene that are responsible for its endometrium-specific expression. To evaluate the generality of these findings, we have begun cloning the promoter regions of potential endometrial markers, including the rat, mouse, and human uteroglobin gene. In the rat, expression of the uteroglobin-like gene, CC10, is dominant in the lung but is also observed in the endometrium of progesterone treated animals. A comparison of the 5'-flanking sequence of the rat and rabbit uteroglobin gene resulted in the detection of similarities and differences that could explain their differential expression in vivo. To substantiate these findings we have established several cell lines from rat endometrium using murine retroviral vectors containing a positive selection marker and various viral oncogenes, such as SV40 large T antigen, adenovirus E1A, and Ha-ras. Cell lines immortalized by SV40 T-antigen were subsequently transformed with the Ha-ras oncogene. Several cell lines exhibit properties of epithelial endometrial cells. Two cell lines generated with a temperature sensitive mutant of the SV40 large T-antigen grow as transformed cells at the permissive temperature, but differentiate upon shifting to the non-permissive temperature. These rat endometrial cell lines should be useful for the analysis of endometrium-specific gene expression and as model systems for endometrial carcinoma.
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PMID:Expression of the uteroglobin promoter in epithelial cell lines from endometrium. 206 10

The molecular genetics of human endometrial carcinoma have yet to be defined to any significant extent. Cell lines from 11 endometrial carcinomas were examined for alterations in proto-oncogenes that might predictably be present, based on existing data from the better-characterized human carcinomas of the uterine cervix, ovary, and breast. Codons 12, 13, and 61 of the Ha-ras, Ki-ras, and N-ras genes were examined for possible point mutations, and the c-erbB2/neu, c-myc, and epidermal growth factor receptor (EGFR) genes were examined for amplification or overexpression. Ras mutations were found in seven of 11 (64%) tumors, including three in codon 61 of Ha-ras (CAG----CAT) and four in codon 12 of Ki-ras (GGT----GAT in two and GGT----GTT in two). No evidence was found for amplification or overexpression of the c-erbB2 or EGFR genes in any tumor. One tumor contained amplified c-myc sequences and exhibited relative overexpression of c-myc. These data suggest that the amplification or overexpression of several proto-oncogenes frequently observed in other human gynecologic and breast tumors are not prevalent in endometrial carcinoma and that ras gene mutations are relatively common in this tumor type.
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PMID:Analysis of oncogene alterations in human endometrial carcinoma: prevalence of ras mutations. 206 24

The role of cellular oncogenes in the development of epithelial tumors of the human female reproductive tract has not previously been extensively studied. DNAs isolated from ten human uterine, 13 ovarian, and four cervical neoplasms and from three cell lines derived from endometrial adenocarcinoma were investigated by dot blot hybridization after polymerase chain reaction amplification of ras gene sequences and in some cases by NIH 3T3 transfection. Transforming activity was found in two of nine endometrial adenocarcinomas, but none of seven ovarian carcinomas and none of four cervical carcinomas showed transforming activity. K-ras sequences with a GGT----GAT mutation in codon 12 were demonstrated in both transformants derived from endometrial carcinoma. K-ras codon 12 mutations were similarly detected in six of 13 endometrial carcinomas (one GAT and GCT, one GTT and GCT, two GAT, two GTT) and two of 13 ovarian tumors (GAT and GCT, GAT), both mucinous adenocarcinomas. Point mutation of K-ras in codon 12 is thus comparably frequent in uterine endometrial carcinomas and in colorectal carcinomas and may have similar significance as an event that contributes to progression of these tumors. Cervical carcinomas and ovarian tumors in general, with the possible exception of mucinous adenocarcinoma of the ovary, do not appear to have this characteristic.
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PMID:K-ras activation in neoplasms of the human female reproductive tract. 220 77

Mutations of the Ki-ras oncogene in endometrial carcinoma have been reported in Japan, but the prevalence and clinical significance of such mutations in the United States remains unclear. DNA extracted from paraffin sections of 112 carcinomas of the endometrium was amplified by the polymerase chain reaction with mismatched primers that generated a BstNI recognition site with the wild-type codon 12. Loss of this recognition site indicating Ki-ras codon 12 mutations was observed in 13 tumors (11.6%), including 11 endometrioid carcinomas, one undifferentiated carcinoma, and one carcinosarcoma. None of 17 papillary serous-clear cell carcinomas contained Ki-ras codon 12 mutations. These mutations were confirmed and characterized by direct sequencing. We found no evidence of correlation of the presence of Ki-ras mutations with stage, grade, depth of invasion, or clinical outcome. Our results indicate that Ki-ras oncogene mutations in carcinoma of the endometrium may be less prevalent in the United States than in Japan.
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PMID:Mutations of the Ki-ras oncogene in carcinoma of the endometrium. 785 26

Alterations of the retinoblastoma (Rb) gene were evaluated in nine primary endometrial adenocarcinomas that we had previously analyzed for the presence of Ki-ras activations and p53 alterations and in three endometrial carcinoma cell lines. Loss of mRNA expression in the Rb gene was detected in two of the 12 tumors. Internal deletions of Rb cDNA were observed in two tumors; one was a deletion of exon 21 in a primary carcinoma, and the other was a deletion of exon 8 in one allele in one cell line. Loss of heterozygosity of the Rb gene, which was detectable by polymorphisms in introns 1 and 17, was analyzed using polymerase chain reaction-restriction fragment length polymorphism analysis in 29 endometrial carcinomas. Of 13 heterozygous cases, two cases (15%) showed loss of heterozygosity. We therefore suggest that alteration of the Rb gene, as well as activation of the Ki-ras gene and alterations of the p53 gene, plays a significant role in the etiology of endometrial adenocarcinoma.
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PMID:Alterations of the Rb gene and its association with Ki-ras activation and p53 inactivation in endometrial adenocarcinoma. 810 95

Endometrial carcinoma is theorized to arise from a series of somatic mutations which alter benign endometrium to progressively less differentiated histological lesions. One genetic alteration implicated in the carcinogenesis of endometrial cancer is the mutational activation of the c-Ki-ras oncogene. This study characterizes the frequency and the topographical distribution of activated c-Ki-ras alleles in endometrial carcinoma. Sixty formalin-fixed, paraffin-embedded endometrial cancer specimens were screened for point mutations at codons 12 and 13 of the c-Ki-ras oncogene by polymerase chain reaction and allelic specific oligomer dot-blot hybridization. c-Ki-ras mutations were identified in nine of 60 (15%) tumor specimens. Five cases resulted in G to A transitions, three in G to T transversions, and one in a G to C transversion. These nine mutant tumors were analyzed by selective UV radiation fractionation and polymerase chain reaction for the presence of activated c-Ki-ras alleles in cell populations of various histological phenotype. In eight tumors, c-Ki-ras mutations were uniformly present in the carcinoma cells. One tumor exhibited heterogeneous mutational activation, with mutant c-Ki-ras alleles detected in only grade 2 carcinoma cells but not grade 1 carcinoma cells. c-Ki-ras mutations were present in adjacent hyperplasia with atypia but absent from hyperplasia without atypia. With rare exception, c-Ki-ras activation appears to be an early oncogenic event since it is homogeneously present in premalignant and malignant endometrial tissues.
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PMID:Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. 813 66

Monoclonal antibody rp-28 directed against the ras gene product p21 has been used to evaluate ras p21 expression in endometrial lesions. Endometrial cancer showed a variable reactivity according to histological type: in well differentiated adenocarcinoma 63% were positive (12/19); in moderately differentiated adenocarcinoma 53% were positive (8/15); in poorly differentiated adenocarcinoma 40% were positive (2/5). The staining intensity of ras p21 seemed to be stronger in the more differentiated types of endometrial carcinoma. In endometrial carcinoma with premenopausal women, 27% were positive (3/11), and with postmenopausal women 71% were positive (20/28). The difference between premenopausal and postmenopausal groups was statistically significant (Mantel-Haenszel procedure, M-H chi 2 = 6.765, P < 0.01). The results suggest the existence of different carcinogenetic mechanisms in these two groups of endometrial cancer.
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PMID:Immunohistochemical analysis of ras oncogene product p21 in human endometrial carcinoma. 827 32


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