Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported (T. Enomoto et al., Cancer Res., 50: 6139-6145, 1990; T. Enomoto et al., Cancer Res., 51: 5308-5314, 1991) a significant frequency of activating point mutations in codon 12 of the c-K-ras-2 protooncogene in endometrial adenocarcinoma and its premalignant precursor lesions (series 1 and 2). To reveal the role of the p53 tumor suppressor gene in the development of endometrial adenocarcinoma and to study the association of p53 alterations with K-ras activation, an additional 28 endometrial adenocarcinomas and an additional 11 premalignant atypical uterine hyperplasias (series 3), as well as 12 cases of endometrial adenocarcinoma (10 having K- or N-ras activation) and 2 cases of atypical hyperplasia from series 1 and 2, were screened for the presence of p53 alterations. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 6 of 19 (32%) informative cases of endometrial adenocarcinoma and 1 of 4 (25%) informative cases of endometrial atypical hyperplasia by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by single-strand conformation polymorphism analysis of PCR-amplified DNA fragments. Mutations were found in 9 of 40 (23%) endometrial adenocarcinomas and 1 of 13 (8%) atypical hyperplasias that were studied. Mutations in p53 were significantly more frequently found in clinical grade 3 (G3) cancers (6 of 14, 43%) than in G1-G2 cancers (3 of 26, 12%) (P = 0.033). Mutations were subsequently confirmed by direct sequencing. Single missense base substitutions were detected in 6 cases of endometrial carcinoma and in one case of atypical hyperplasia. Deletions of a single base and of 2 bases were each detected in single cases of endometrial carcinoma, and a single base insertion was found in a third case. Point mutations in K-ras were also identified in tumors of series 3 by direct sequencing of PCR-amplified DNA fragments of exons 1 and 2. Point mutations in codons 12 and 13 in K-ras were detected by direct sequencing of PCR-amplified DNA in 7 of 28 adenocarcinomas in series 3, but none were found in exon 2 (codons 59.63. The spectrum of point mutations in p53 in endometrial adenocarcinomas was almost identical to what we found in K-ras in series 1 and 2 and in series 3, suggesting the possible role of a mutagen that might be responsible for mutations in both K-ras and p53.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations of the p53 tumor suppressor gene and its association with activation of the c-K-ras-2 protooncogene in premalignant and malignant lesions of the human uterine endometrium. 838 72

Mutations in the p53 gene are associated with a wide variety of human malignancies. Point mutation in one allele and loss of the remaining one generally lead to inactivation of p53 protein. A high frequency of allelic losses corresponding to the 17p13.3 region that contained the p53 gene sequence was also noted in human endometrial carcinoma. Thus, in order to confirm involvement of the p53 gene in endometrial carcinogenesis, we searched for nucleotide sequence change in this gene in 42 endometrial carcinomas that had been subjected to previous LOH analyses. Using the polymerase-chain-reaction-single-strand conformation polymorphism (PCR-SSCP) method, we detected p53 gene mutations in 4 specimens. Two adenocarcinomas with allelic loss on 17p contained a mutant p53 gene in the allele that was retained. One specimen with a p53 gene mutation contained a 17q deletion but was uninformative for LOH on 17p. p53 gene mutation was also noted in the remaining stage-I carcinoma, though the 17p deletion was not detected in the previous LOH examination. However, 5 specimens with the LOH on 17p retained the wild-type p53 gene. In the remaining 33 specimens, both alleles of p53 gene seemed to be normal. The mutations observed in 2 specimens (cases 10 and 24), involving C-to-T and T-to-G substitutions, were located in a highly conserved region. However, the mutations identified in the remaining 2 cases (29 and 35) were at regions positioned outside conserved stretches.
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PMID:Involvement of p53 gene mutations in human endometrial carcinomas. 847 53

We examined the immunohistochemical localization of p53, a tumor suppressor gene, in thirty-three specimens of uterine endometrial carcinoma which included one case of carcinosarcoma, eleven specimens of endometrial hyperplasia and ten specimens of normal endometrium. We also analyzed the association between the immunolocalization of p53 protein and the clinical and pathological parameters of endometrial concern. We also determined whether p53 mRNA is overexpressed in these specimens by in situ hybridization and simultaneous immunohistochemistry and in situ hybridization. Immunohistochemistry was performed using the monoclonal antibodies pAbDO-7 and pAb1801, and polyclonal antibody pAbCM-1. Immunoreactive p53 was observed in the nuclei of the cancer cells in 15/33 (45%) by pAbDO-7, 11/26 (42%) by pAb1801, and 16/33 (48%) by pAbCM-1. No p53 immunoactivity could be detected in either hyperplasia or normal endometrium except for a case in which the endometrium was in the secretory phase. There was no significant relationship between p53 immunostaining as determined by pAbDO-7, and age, clinical stage, histological grade or depth of myometrial invasion. We employed the 35S-labeled antisense single stranded synthetic oligonucleotide probe, ON102, to perform in situ hybridization and simultaneous immunohistochemistry and in situ hybridization. In every case of endometrial carcinoma studied, no significant accumulation of the p53 hybridization signal was observed in carcinoma cells. This indicated that overexpression of p53, as observed by immunohistochemical staining, is not due to an increase in the steady-state level of p53 mRNA in carcinoma cells. These results suggest that immunostaining of p53 is associated with the malignant phenotype, but does not correlate with the biological behavior of human endometrial carcinoma.
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PMID:Immunohistochemical and in situ hybridization analysis of p53 in human endometrial carcinoma of the uterus. 851 43

A solitary metastasis in the left tarsus led to the diagnosis of primary endometrial cancer in a 61 year-old patient with no history of postmenopausal bleeding. Lower leg amputation, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy were performed. Histopathology showed a well-differentiated endometrioid adenocarcinoma of the uterus with a low mitotic rate, but infiltration of the outer third of the myometrium and lymph vessel invasion (FIGO Stage IVb). Immunostaining was positive for progesterone receptors, but negative for estrogen receptors and p53. The lymph nodes were free of metastases. Ascites was positive for malignant cells. Postoperatively the patient received carboplatin, cyclophosphamide and medroxyprogesterone acetate and is alive with no evidence of disease 10 months after diagnosis.
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PMID:Solitary metastasis in the tarsus preceding the diagnosis of primary endometrial cancer. A case report. 854 5

Autocrine and paracrine interactions between cells are important homeostatic mediators in normal tissues. Alterations to growth factor signalling pathways are likely to play a role in multistep carcinogenesis. In this study normal human endometrial epithelial cells (NHEC) after 3 days in culture were treated with serum-free medium conditioned for 24 h by log phase or confluent cultures of established RL95-2, HEC1A, or AN3CA endometrial carcinoma (EC) cell lines. By day 4, NHEC treated with either log phase or confluent conditioned medium (CM) showed a significant decrease (approximately 50-90% of control) in [3H]thymidine ([3H]TdR) incorporation. DNA synthesis was inhibited more by confluent than by log phase CM. By day 7, NHEC treated with CM exhibited fewer colonies per culture, fewer cells per colony, and an increased percentage of single cells. Several growth-regulatory gene products found in the nucleus or at the cell membrane have been shown to be expressed differently in normal and transformed cells. We selected the p53 and c-Ha-ras p21 proteins to further investigate the mechanism of alteration of proliferation in cells treated with carcinoma CM. Thus, by day 7, the percentage of NHEC with nuclear localization of wild type p53 (wt p53) was elevated by treatment with CM. In contrast, CM-treated EC cells continued to proliferate, and showed a decrease in the percentage of cells expressing nuclear wt p53 and an increase in the cytoplasmic expression of c-Ha-ras p21. Our studies show that EC cell lines release factors which inhibit the proliferation of NHEC, thus favoring the proliferation of EC cells.
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PMID:Human endometrial carcinoma cells release factors which inhibit the growth of normal epithelial cells in culture. 860 6

Defective DNA mismatch repair in neoplasia is manifested by extra, aberrant bands within multiple microsatellite markers. The replication error (RER) phenotype is present in most colorectal and endometrial carcinomas in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. In addition, a minority of sporadic colorectal and endometrial carcinomas are RER positive. RER in sporadic colorectal carcinomas has been associated with improved prognosis, but its clinical significance in sporadic endometrial cancer has not been characterized. We analyzed DNA extracted from 109 formalin-fixed sporadic endometrial carcinomas for microsatellite instability. The RER-positive phenotype was demonstrated by microsatellite instability in more than one of the eight dinucleotide markers tested. RER was correlated with pathological and clinical parameters as well as with immunohistochemical staining for the p53 gene product and alterations in codon 12 of Ki-ras. Nine percent of the endometrial carcinomas were RER positive, and RER was significantly associated with high grade and adverse outcome. We found no significant correlation of RER with histological subtype, stage, depth of invasion, mutations in the 12th codon of Ki-ras, or p53 immunoreactivity. We conclude that the RER phenotype is present in a minority of sporadic endometrial carcinomas and is associated with high grade and poor prognosis.
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PMID:Clinical and pathological significance of microsatellite instability in sporadic endometrial carcinoma. 862 34

Forty-two cases, including 21 uterine papillary serous carcinomas (UPSC) and 21 age-, nuclear-grade-, and clinical-stage-matched uterine endometrioid carcinomas (UEC), were studied immunohistochemically for p53 and bcl-2 in archival paraffin-embedded tissue. Compared to UEC (28.6% positive), UPSC (71.4% positive) had a significantly higher frequency of p53 overexpression (P = 0.005); furthermore, in a clinical-stage-matched fashion, a higher frequency of p53 overexpression was found in early-stage cases (P = 0.032), but not in late-stage cases. In a nuclear-grade-matched comparison, no statistical difference in p53 overexpression was identified between the two subtypes, although UPSC had stronger p53 immunoreactivity than UEC. Of UPSC, no difference in p53 overexpression was detected between tumors of early and late stages; additionally, in 5 cases, there was an abrupt transition from nonstaining morphologically benign glands to uniformly positive p53 nuclear staining in regions of intraepithelial carcinoma. Conversely, in UEC, there was a significant difference in p53 immunostaining between tumors of early and late stages (P = 0.01); no case had an abrupt transition for p53 immunostaining. For bcl-2 immunostaining, UEC had a significantly higher immunohistochemical staining score than did UPSC (P = 0.0002). In general, the staining intensity of bcl-2 diminished progressively from proliferative phase and hyperplastic endometrium to UEC and then to UPSC, with 3 of 21 (14.3%) UPSC being negative. These results suggest that p53 alteration may be an early event in the development of UPSC and may be related to its clinical aggressiveness, while it is a late event in UEC. Early detection of p53 nuclear accumulation may help to identify precursor lesions of UPSC. bcl-2 persistence is frequently associated with endometrial carcinoma, and failure to inactivate bcl-2 expression probably is related to the development of endometrial carcinoma.
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PMID:p53 overexpression and bcl-2 persistence in endometrial carcinoma: comparison of papillary serous and endometrioid subtypes. 862 27

The aim of this study was to evaluate the presence and distribution of p53 alterations in pure endometrioid adenocarcinomas (n = 120) of different grades and stages, as opposed to normal endometrium (n = 13) and various risk groups of hyperplasia (n = 39). All samples were initially analysed by immunohistochemistry with the monoclonal antibody Ab-6. Normal endometria were negative. With increasing degrees of malignancy, the number of cases with p53 accumulation rose and ranged from 9% to 18% in hyperplasia, through 25% in low-grade carcinomas (G1), to 69% in high-grade carcinomas (G3). This increase was also seen when comparing tumours by stage. Of carcinomas in stage IA, only 17% showed p53 immunostaining, in contrast with 72% in stage IC. Of this material, 34 carcinomas and 8 hyperplasias were analysed for p53 mutations in exons 5-8 by means of polymerase chain reaction and temperature-gradient gel electrophoresis (TGGE). In none of 5 hyperplasia and 6 of 12 carcinomas showing p53 accumulation by immunohistochemistry, p53 mutations were detected by TGGE. In contrast, 4 of 22 carcinomas harboured mutant p53 but were negative by immunohistochemistry. Immunohistochemical and molecular investigations revealed that p53 alterations are related to the standard prognostic markers of endometrial cancer, i.e. grading and staging. TGGE, an indirect screening procedure for p53 mutations, is used to detect the type of p53 alteration and may provide additional insight into the complex figure of p53 abnormalities in the development and progression of malignant endometrial lesions.
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PMID:Comparison of benign and malignant endometrial lesions for their p53 state, using immunohistochemistry and temperature-gradient gel electrophoresis. 864 68

In a histopathological review of 266 women with stage I-IV endometrial carcinoma, the prognostic significance of uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CCC) of the endometrium was compared with that of ordinary adenocarcinoma and adenoacanthoma. UPSC and CCC were diagnosed in 31/266 (12%) and 6/266 (2%) of the patients respectively. The median follow-up time was 79 months (range 3 to 133 months). 49% of the patients with UPSC or CCC died of their cancer compared with 31% in the adenocarcinoma + adenoacanthoma group (RH=2.25; p=0.0022). Strong expression of the mutated p53 gene product was significantly more common in the UPSC + CCC group than in the reference group (64% vs. 19%), (p<0.0001). In a Cox multivariate analysis including histopathological and clinical variables, UPSC and CCC were still significant predictors of survival (p<0.05). When nuclear grade was added to the analysis, UPSC + CCC as well as the degree of differentiation lost most of their prognostic impact. In a final multivariate analysis, DNA ploidy was found to be the strongest predictor of outcome besides age and clinical stage.
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PMID:Endometrial carcinoma: the prognostic impact of papillary serous carcinoma (UPSC) in relation to nuclear grade, DNA ploidy and p53 expression. 868 48

The usefulness of prognostic factors in gynecological cancer was evaluated using the oncogenes, tumor suppressor genes and DNA viruses detected with the molecular biological technique. In uterine cervical cancer, HPV types 16 and 18 are considered to have a high oncogenic risk, and are commonly associated with high grade CIN and invasive cancer under persistent HPV infection. C-myc overexpression in advanced stage and p53 mutation in HPV negative case are associated with poor survival. In endometrial cancer, oncogene activation and expression are less frequent than in cervical and ovarian cancer. K-ras point mutation (codon 12) tumors are more aggressive and c-erbB-2 overexpression are associated with metastasis and poor survival. In ovarian cancer, there are numerous abnormalities of oncogenes and tumor suppressor genes. Especially, EGF-R and PDGF-R alpha expression are associated with decreased survival. p53 mutation also decreases survival and response to chemotherapy. Recently. MSH2 (Lynch II syndrome) and BRCA1 gene are known to relate with familial ovarian cancer.
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PMID:[Evaluation of prognostic factors in gynecological cancer examined by molecular biological study]. 868 14


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