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)

The p16INK4aa (CDKN2) tumor suppressor gene is altered in several tumor types, but the frequency and mechanism of inactivation are largely unknown for endometrial carcinomas. We therefore wanted to assess the pattern and prognostic impact of p16 protein expression and promoter region methylation in a population-based series of 316 endometrial carcinoma patients with long-term and complete follow-up. Nuclear staining of p16 protein was related to clinicopathological variables, tumor markers, patient survival, and the presence of promoter region methylation. Absent/minimal nuclear staining for p16 protein was found in 14% of the tumors. Methylation of the p16 promoter region was found in only one tumor (0.7%) in a subset of 138 cases studied. This tumor lacked nuclear p16 protein expression as well. Loss of nuclear p16 staining was significantly associated with increased age, high FIGO (International Federation of Gynecology and Obstetrics) stage, serous papillary or clear cell histological types, high histological grade, aneuploidy, low estradiol and progesterone receptor concentrations, high expression of Ki-67, high intratumor microvessel density, and strong nuclear p53 protein expression. The 5-year survival was 47% for patients with absent/minimal nuclear p16 expression (n = 39) compared with 81% for patients with moderate/high nuclear p16 expression (n = 247; P < 0.0001). In Cox proportional hazards regression analysis, nuclear p16 expression showed an independent prognostic impact in addition to FIGO stage, age, Ki-67 expression, and microvessel density, with an adjusted hazard ratio of 2.9 (95% confidence interval, 1.3-6.5). The other variables lost their prognostic impact when nuclear p16 staining was added to the Cox model. In conclusion, loss of nuclear p16 protein expression was associated with aggressive endometrial carcinomas and high proliferative activity (Ki-67) and was found to represent a strong and independent prognostic indicator. Methylation of the promoter region seems to be an uncommon mechanism of p16 inactivation in endometrial carcinoma.
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PMID:Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. 1065 44

Papillary serous endometrial carcinoma is an aggressive tumor characterized by late-stage presentation, i.p. spread, and poor prognosis. It is histologically similar to serous papillary carcinoma of the ovary. Preclinical studies have shown that adenovirus-mediated expression of p53 in ovarian cancer cell lines causes growth inhibition and apoptosis in vitro and in vivo. Such studies provide the rationale for Phase I Adp53 gene therapy clinical trials in ovarian cancer. In the present study, we compared the efficacy of adenoviral vectors containing p53 (Adp53) or p21 (Adp21) in a papillary serous endometrial tumor cell line (SPEC-2) that contains mutated p53. Growth assays revealed that both Adp53 and Adp21 were efficacious in decreasing cell proliferation as assessed by anchorage-dependent and anchorage-independent growth assays. However, as compared with Adp53, the effects of Adp21 tended to be more transient and less marked. Strikingly, Adp21, but not Adp53, induced a G1 arrest in SPEC-2 endometrial adenocarcinoma cells. In contrast, as assessed by induction of hypodiploid peaks, free DNA ends detected by a terminal deoxynucleotidyl transferase-based assay, and annexin V positivity, p53 was more effective than p21 in inducing cell death by apoptosis. Compatible with the more efficient induction of apoptosis, Adp53, but not Adp21, induced a marked increase in expression of the preapoptotic molecule BAX without a concomitant change in expression of the antiapoptotic mediator Bcl-2. The differential effects of Adp53 and Adp21 on cell cycle progression and apoptosis may be related to the reversibility of p21-induced cell cycle arrest and the irreversibility of p53-induced apoptosis. Thus, at least in the papillary serous endometrial carcinoma cell line SPEC-2, Adp53 may be more effective than Adp21 as a gene therapeutic. Nevertheless, these preclinical studies suggest that papillary serous endometrial carcinoma is a potential target for p53- or p21-mediated gene therapy.
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PMID:Adenovirus-mediated expression of p53 or p21 in a papillary serous endometrial carcinoma cell line (SPEC-2) results in both growth inhibition and apoptotic cell death: potential application of gene therapy to endometrial cancer. 1065 59

The aim of the study was to investigate p53 protein expression by the Western blotting technique (estimated by integrated optical density - IOD) in normal (n = 13) and neoplastic (n = 40) human endometrial tissues as well as in a case of uterine carcinosarcoma and in a specimen of the botryoid sarcoma of the uterine cervix. p53 protein levels were correlated with patients' age as well as with conventionally used clinicopathological features of the endometrial neoplasm. A statistically significant difference was noted in p53 levels in the nuclear, but not in the cytoplasmatic, fraction between the normal endometria and endometrial cancer tissues (P < 0.0001). In the neoplastic endometria, nuclear p53 protein expression was higher than in cytoplasmatic fraction, and the difference was significant (P < 0.05). Higher nuclear p53 protein levels correlated with advanced histological grading of endometrioid endometrial carcinomas, but no relationship was noted between p53 protein expression and patients' age, clinical stage, histological type or depth of myometrial invasion. A case of uterine carcinosarcoma and a specimen of a botryoid sarcoma of the uterine cervix expressed nuclear p53 oncoprotein (57 IOD and 89 IOD, respectively). In conclusion, we found a statistically higher nuclear p53 levels in malignant as compared to normal human endometrial specimens by the Western blotting technique. Although there were no significant differences between p53 expression and clinicopathological features of the neoplasm (except poor histological grading), further studies are necessary to evaluate the influence of p53 nuclear/cytoplasmatic levels on the clinical outcome of Polish patients suffering from endometrial cancer.
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PMID:p53 protein detection by the western blotting technique in normal and neoplastic specimens of human endometrium. 1069 97

Historical observations have suggested that endometrial carcinomas vary in histopathologic appearance and clinical features. More recent, systematic studies have provided epidemiologic, clinicopathologic, and molecular support for these observations. Specifically, studies suggest that the most common type of endometrial carcinoma, endometrioid adenocarcinoma, develops from endometrial hyperplasia in the setting of excess estrogen exposure and usually pursues an indolent clinical course. In contrast, a minority of endometrial carcinomas, best represented by serous carcinoma, do not seem to be related to estrogenic risk factors or elevated serum hormone levels, and these tumors seem to develop from atrophic rather than hyperplastic epithelium. We have proposed that serous carcinomas develop from "endometrial intraepithelial carcinoma," a lesion representing malignant transformation of the endometrial surface epithelium. Whereas endometrioid carcinoma and endometrial hyperplasia are associated with microsatellite instability and ras and PTEN mutations, serous carcinoma and endometrial intraepithelial carcinoma are associated with p53 mutations and abnormal accumulation of p53 protein. Based on these data regarding the pathogenesis of endometrioid and serous carcinoma, we have proposed a dualistic model of endometrial carcinogenesis incorporating a "classic" estrogen-driven pathway and an "alternative" pathway seemingly unrelated to hormones. It is hoped that further studies may permit the extension and modification of this model and that these advances will lead to improved diagnosis, management, and prevention.
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PMID:Theories of endometrial carcinogenesis: a multidisciplinary approach. 1075 40

Sera from patients with gynaecological cancer including the ovary, endometrium or cervix were examined for p53 protein, using the Pantropic p53 quantitative ELISA. Patients with benign gynaecological pathologies were included as a control group. p53 values ranged from undetectable to high levels of the protein (range: 0-531 pg/ml). Using the value of 200 pg/ml as the cut-off, p53 serum levels were found to be elevated in 23% of the patients with ovarian cancer, in 16% of the patients with endometrial cancer and in 14% of the patients with cervical cancer. In the control group, increased serum p53 levels were found in 3.3% of patients. No differences were observed among the groups with different types of cancer or at different stages, but the differences between the cancer groups and the control group were statistically significant. Our results suggest that serum p53 evaluation could be an adjunctive tool to the diagnostic laboratory tests for preoperatively gynaecological cancers and both a competitive and alternative useful procedure for the detection of p53 gene mutations.
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PMID:Serum evaluation of P53 protein in patients with gynaecological cancer. 1081 Mar 93

Alterations in the cellular genome affecting the expression or function of genes controlling cell growth and differentiation are considered to be the main cause of cancer. Genes that cause cancer are of two distinct types: oncogenes and onco-suppressor genes. The normal proto-oncogene can be converted into an active oncogene by deletion or point mutation in its coding sequence, gene amplification, and by specific chromosome rearrangements. Mutations and abnormal expression in ras, myc, c-erbB-2, and other oncogenes have been reported in several types of gynecological cancer. Onco-suppressor genes are involved in gynecological cancer, their functions are localized in different phases of the cell cycle. Structural changes and deletions of these genes can cause cancer. Mutations in the p53, BRCA1, DCC, and PTEN genes have been reported in gynecological cancers such as ovarian, cervical, and endometrial cancer. Human papillomaviruses are of major interest because specific types (HPV-16, -18, and several others) have been identified as causative agents in at least 90% of cancers of the cervix. In this study we summarize the available information regarding the implication of specific oncogenes, onco-suppressor genes, and HPV in the development of female genital malignancies.
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PMID:Molecular basis of gynecological cancer. 1081 92

Abnormalities in structure and expression of the fragile histidine triad transcription (FHIT) gene have been reported in a variety of cancers, including endometrial cancers. A good correlation between FHIT gene alteration and loss of Fhit expression was observed in endometrial cancers, although those are the selected cases. Therefore, we investigated the association of Fhit expression with clinicopathological features in 111 cases of endometrial cancer. Loss of Fhit expression was associated with high malignant potential, including extensive muscular invasion, advanced surgical stage, high histological grade, nonendometrioid types of adenocarcinoma, negative estrogen receptor status, and p53 overexpression. The presence of personal cancer history was also related to the loss of Fhit with a marginal significance. Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that decreased expression of Fhit was associated with a poor outcome. However, multivariate analysis using the stepwise Cox proportional hazard model showed that whereas lymph node metastasis, advanced stage, and high tumor grade were related to poor survival rates, loss of Fhit expression was not. Consequently, loss of Fhit expression is associated with advanced surgical stage and does not appear to be an independent prognostic factor in endometrial cancers, although a still larger sample of patients will be required to asses this issue definitively.
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PMID:Clinicopathological significance of fragile histidine triad transcription protein expression in endometrial carcinomas. 1087 85

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

Although several studies have reported that p53 overexpression is associated with poor survival from endometrial cancer, this relationship might be confounded by a number of possible factors. The objective of this study was to examine the prognostic role of p53 overexpression in endometrial cancer when a panel of well-selected potential confounding factors were controlled. One hundred and twenty-five endometrial cancers were examined for p53 overexpression by immunohistochemistry (IHC). Demographic and clinical data, including age at diagnosis, race, residence, tumor grade, surgical stage, and other possible confounding factors for endometrial cancer such as diabetes, family history of cancer, hypertension, hormone replacement therapy (HRT), and obesity were collected from medical charts and pathologic reports. Survival status was determined at the end of follow-up. The Kaplan-Meier method was used to derive the survival curve, while the log-rank test was used to compare curves for two or more groups of patients. The proportional hazards regression model was used to obtain maximum likelihood estimates of relative risks (RR) and their 95% confidence intervals. Compared to the p53 nonaltered group, the presence of p53 overexpression in endometrial carcinoma was related to significantly decreased patient survival. High nuclear grade and high FIGO stage were associated with poor survival. No obvious association was found between survival and study site, race, age, and other potential risk factors of endometrial cancer. Only two variables (p53 and stage) were significantly associated with poor survival in the multivariate proportional hazards analysis. Overexpression of p53 was found to be the most significant predictor of specific survival. The relative risk for p53 overexpression was 7.46 (95% CI: 4.26-13.1) and for late stage was 4.35 (95% CI: 1.91-9.92). We conclude that p53 overexpression is the most important predictor for patient survival when a panel of well-selected potential confounding factors are taken into account. Patients with endometrial cancers who have p53 overexpression have a seven-fold higher risk of dying from disease compared to those without p53 overexpression. Whether detection of p53 alteration may serve as an indicator of high-risk patients for whom more aggressive adjuvant chemotherapy may be considered needs to be explored in the future.
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PMID:p53 as a significant prognostic marker in endometrial carcinoma. 1124 Jun 63

Uterine papillary serous carcinoma (UPSC) is a clinically aggressive and morphologically distinctive variant of endometrial carcinoma that has been recognized recently as a distinct entity. The association between radiation therapy (RT) and UPSC is rarely described in the literature. We describe the clinicopathologic features of a 71-year-old patient with UPSC that developed 15 years after radiation therapy for squamous cell carcinoma of cervix, stage IIB. In the subtotal hysterectomy specimen the endometrium was irregular with multifocally raised masses. Microscopically, the tumor was composed of high-grade papillary serous carcinoma focally admixed with solid transitional cell carcinomatous areas and multifocal intraepithelial carcinoma in adjacent atrophic endometrium. The tumor exhibited diffuse infiltrative growth with frequent lymphatic tumor emboli in the myometrium. Immunohistochemical staining for p53 and c-erbB-2 were positive in about 70% of the tumor cells. Carcinoembryonic antigen (CEA) was focally positive. Ki-67 positive cells were present in about 60% of the tumor cells. The tumor directly extended to the cervix and perirectal soft tissue and metastasized to the omentum. Intraoperative pelvic washing cytology was positive for papillary adenocarinoma cells. The possible etiologic role of radiation is discussed, and the literature on endometrial carcinomas developing after RT is reviewed.
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PMID:Uterine papillary serous carcinoma following radiation therapy for carcinoma of cervix: a case report. 1124 Jun 83


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