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 roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tumours. Reduced expression of p16 protein, detected by immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the 5'-CpG island of the p16 gene was detected in only one of 32 (3%) cervical tumours and none of 26 endometrial tumours. Homozygous p16 gene deletion, evaluated by differential PCR analysis, was found in four of 40 (10%) cervical tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was found in three of 40 (8%) cervical tumours and one of 38 (3%) endometrial tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40 (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis-sense mutations, one in codon 74 (CTG-->ATG) and one in codon 129 (ACC-->ATC), both in cervical carcinomas, and the other was in codon 127 (GGG-->GAG) in an endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA-->TGA), in an endometrial carcinoma. The remaining two were silent somatic cell mutations, both in cervical carcinomas, resulting in no amino acid change. These observations suggest that inactivation of the p16 gene, either by homologous deletion, mutation or loss of expression, occurs in a subset of uterine tumours.
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PMID:Alteration of p16 and p15 genes in human uterine tumours. 1040 54

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

We analysed p16 gene alteration and p16, cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, cyclin D2, cyclin D3 and retinoblastoma protein (pRb) expression in ten normal endometriums (PE), 18 endometrial hyperplasias (EH) and 35 endometrial cancers (EC). Two of ten PE (20%), nine of 18 EH (50.0%) and 29 of 35 EC (82.9%) exhibited p16 nuclear staining. p16 expression was significantly higher in EC than EH (P = 0.0119). In the six p16 (-) EC, one was considered to have reduced gene dosage consistent with possible homozygous deletion of the CDKN2 gene and three had methylation in 5'CpG island in the promoter region of the p16 gene, whereas none showed such reduced gene dosage and four had methylation in the nine p16 (-) EH. Strong CDK4 staining was observed in 12 of 35 EC (34.3%) and one of 18 EH (5.6%). The strong expression of CDK4 was higher in EC than in EH (P = 0.0399). The expression of CDK4 was higher in EH than PE (P = 0.0054). The abnormalities of p16-cyclin D/CDK-pRb pathway were detected in 18 of 35 EC (51.4%). In conclusion, the expression of p16 and CDK4 may be an early event in the neoplastic transformation of endometrial cancer.
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PMID:The role of p16-cyclin d/CDK-pRb pathway in the tumorigenesis of endometrioid-type endometrial carcinoma. 1068 82

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

Endometrial carcinoma is today among the most common gynecologic malignancies in industrialized countries. In order to improve the treatment and follow-up of these patients, various prognostic factors have been extensively studied. Patient age, stage of disease, histologic type and histologic grade have been shown to influence survival significantly, and the prognostic impact of these traditional clinicopathologic variables is well established. In addition, parity, hormone receptor concentration in the tumor, DNA ploidy and morphometric nuclear grade have all been found to influence prognosis. Information about DNA ploidy has especially been used in the clinical situation to determine individualized treatment. The prognostic significance of markers for tumor cell proliferation, cell cycle regulation (p53, p21 and p16) and angiogenesis is discussed as well as the molecular basis of endometrial carcinoma. In conclusion, several prognostic markers have been identified. It is likely that the information derived from these tumor biomarkers will reduce the need for extensive surgical staging and adjuvant treatment in endometrial carcinoma.
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PMID:Molecular pathogenesis and prognostic factors in endometrial carcinoma. 1258 34

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

The tumor suppressor gene p16, located on chromosome 9p21, encodes the cell cycle regulatory protein, p16. Inactivation of the p16 gene could lead to uncontrolled cell growth. It was examined that methylation of the p16 gene 5'CpG island of the tumor suppressor gene may be an important mechanism for transcriptional inactivation. In order to determine the role of methylation status of the 5'CpG island and abnormal expression of incarcinogenesis of endometrial carcinoma (EC), Methylation-Specific PCR (MSP) was used to determine the methylation status of p16 gene 5'CpG islands of 62 cases of EC. Loss or decrease of p16 expression was analyzed by immunohistochemistry (IHC) and homozygous deletion of exon1 (E1) and exon2 (E2) was determined by complex PCR. Ten specimens of normal tissues and adjacent tissues of tumor displayed no methylation and showed normal expression of p16. In E1 and E2 of the 62 EC, we found that 24.2% (15/62) were methylated, 54.8% (33/62) lost or reduced p16 expression, 16.1% (10/62) and 30.6% (19/62) had deletions of E1 and E2 respectively. There were 9.68% (6/62) and 46.6% (29/62) deletions of both or either of E1 and E2 respectively. Inactivation of p16 gene is a frequent event and positively correlated with pathological grades and clinical stages in EC. p16 gene methylation was an important event in the development of EC. MSP is an accurate and relatively simple method for evaluating the methylation status of a related gene.
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PMID:[Significance of methylation and abnormal expression of p16 gene in endometrial carcinoma]. 1547 4

Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80-90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1-3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5-10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1 . Other hereditary disorders predisposing to PC include Peutz-Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32-34 mutation, hereditary breast-ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1 , familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis, as well as screening and control, may take place.
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PMID:Familial pancreatic carcinoma in Jews. 1551 47

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

Many endometrial adenocarcinomas, particularly those of endometrioid type, express estrogen receptors (ERs), progesterone receptors (PRs), and vimentin. This typical immunophenotype is frequently considered a standard against which others are compared when immunohistochemistry is used for differential diagnosis. We tested large numbers of endometrial cancers, enriched for high-grade tumors, to determine whether this reported immunophenotype was valid and whether expression differences between types of endometrial carcinoma could be exploited for diagnostic purposes. Immunohistochemical stains were performed on the following types of endometrial cancers using established methodology: International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 endometrioid-42; FIGO grade 3 endometrioid-40; serous-24; clear cell-11; carcinosarcoma-9. In total, 92% of serous carcinomas expressed p16 strongly compared to weak-to-moderate expression of p16 in 7-67% of other tumors (FIGO grades 1 and 2 carcinoma and carcinosarcoma, respectively). A total of 84% of FIGO grades 1 and 2 carcinomas expressed ER compared to 9-54% of other tumors (clear cell and serous carcinomas respectively); 83% of FIGO grades 1 and 2 expressed PR compared to 11-54% of other carcinomas (carcinosarcoma and serous carcinoma, respectively). Most carcinomas were negative for monoclonal carcinoembryonic antigen (mCEA), and those that were positive showed mostly only focal membrane expression. Vimentin was expressed in nearly every tumor. Most tumors were diffusely vimentin positive, but a large range of expression patterns, from focal to diffuse and from weak to strong, was noted. Only 70% of FIGO grades 1 and 2 endometrioid carcinomas and 26% of grade 3 endometrioid carcinomas possessed the reportedly characteristic endometrial cancer immunophenotype p16 (-), ER (+), PR (+), mCEA (-), and vimentin (+). Endometrial cancers demonstrate substantial immunophenotypic diversity that remained apparent even within groups of similar histologic subtype and grade. ER, PR, and p16 expression was more illustrative of tumor type and degree of differentiation than they were of endometrial origin. In contrast, the vimentin-positive/CEA-negative phenotype remained the most constant among all endometrial cancers.
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PMID:Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. 1664 64


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