Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse monoclonal antibodies PAb 240 and PAb 1801 which specifically immunoprecipitate p53 protein, were used to examine 27 fresh ovarian tumours (16 serous adenocarcinomas, six endometrioid carcinomas, one mucinous adenocarcinoma, one mucinous borderline tumour and three benign adenomas). Eleven out of 16 (69%) serous adenocarcinomas and one endometrioid tumour showed positive staining with one or both antibodies and none of the mucinous or benign tumours stained with either antibody. DNA from tumour and peripheral blood leukocytes was used to identify allelic deletions on chromosome 17p in tumours. 11/12 positively staining tumours showed less of heterozygosity (LOH) on 17p at the nearest informative locus to the p53 gene. In this series of ovarian tumours, LOH on 17p correlates closely with the aberrant expression of the p53 protein in a high proportion of advanced stage serous adenocarcinomas. This observation suggests that the p53 tumour suppressor gene is involved in the evolution of epithelial ovarian cancer (EOC) and may have prognostic significance.
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PMID:Overexpression of the p53 protein and allele loss at 17p13 in ovarian carcinoma. 131 Feb 51

The genetic events involved in the development of metastases of epithelial ovarian cancer are largely unknown. One gene postulated to play a role in tumour metastasis suppression is NME1 (nm23-H1), and an inverse relationship between NME1 expression and metastatic potential has been observed for some solid tumours. In this study we have investigated the levels of mRNA expression of the 2 isoforms of the NME gene, NME1 and NME2. A maximum of 45 tumours samples from 33 patients were available for Northern blot analysis. We observed variable levels expression of NME1 and NME2 mRNA. The average level of NME1, but not NME2, mRNA expression was statistically higher in metastatic biopsies when compared with primary tumour biopsies. To examine the possible tumour suppressor gene role of NME1 in ovarian tumours, 76 patients were investigated by Southern blot analysis to determine the rate of allelic deletion. Allele loss at 5 other chromosome 17 loci (D17S5, TP53, NF1, D17S74, D17S4) was also evaluated for many of these 76 patients. Allele loss was observed in 22/30 (73%) informative patients at the NME1 locus. We also observed high rates of allele loss at the other loci evaluated. No correlations with clinical stage, histological subtype or patient survival were observed in either mRNA or DNA analyses. We have established that tumour progression in ovarian cancer is accompanied by over-expression of the NME1 gene; however, despite high rates of allele loss at the NME1 locus, the concept that NME1 may be a candidate tumour suppressor gene in ovarian cancer cannot be confirmed by this study.
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PMID:Increased expression of the NME1 gene is associated with metastasis in epithelial ovarian cancer. 762 7

Frequent loss of heterozygosity has been described on several chromosomes in ovarian carcinoma (OC), but few tumour suppressor genes (TSGs) have been analysed. Mutations in the GTPase-related domain (GRD) of the TSG NF1 have been described in tumours not usually associated with neurofibromatosis type 1 (NF1). We analysed 36 OCs for mutations in this domain using single-strand conformation polymorphism. The NF1-GRD can downregulate the active form of p21RAS and, therefore, we analysed the same tumours for mutations in RASK. No cases of mutations in NF1-GRD were seen, and only two cases of RASK mutations were found. Thus, activation of the RAS signalling pathway by RASK or NF1 mutations does not appear to be common in OC.
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PMID:Mutation analysis of RASK and the 'FLR exon' of NF1 in sporadic ovarian carcinoma. 801 14

Frequent loss of heterozygosity in ovarian carcinoma (OC) has been reported on several different chromosomes. We have studied 27 OCs and corresponding normal tissue for loss of heterozygosity (LOH) using 10 markers detecting polymorphisms on chromosome 5 (two on 5p and eight on 5q). Three tumours showed extra copies, rather than loss, of one homologue. Twelve of 24 remaining tumours showed LOH on 5q (50%), and 8 of 21 on 5p (38%). Of the 12 showing LOH on 5q, 7 showed reduction to homozygosity at all informative markers over the chromosome. The remaining 5 showed LOH over all of 5q. These data are consistent with the localisation of a tumour suppressor gene on 5q involved in OC. A good candidate is the APC gene, which is mutated in a number of adenocarcinoma derived from several tissues and is located at 5q21-22. The APC gene was studied in 40 ovarian tumours, including all the OCs showing LOH, by single-strand conformation polymorphism (SSCP). Analysis of all the exons containing published mutations (approximately 4.7 kb of the cDNA) did not reveal any band shifts that could be attributed to mutations. However, a new polymorphism was detected, as well as 7 known polymorphisms. Together, these data indicate that (1) LOH is common on chromosome 5 in OC, (2) APC is not mutated in OC, and (3) another gene (or genes) on chromosome 5q is responsible for the LOH seen.
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PMID:Loss of heterozygosity on chromosome 5 in sporadic ovarian carcinoma is a late event and is not associated with mutations in APC at 5q21-22. 801 64

Investigation of genetic changes in tumours by loss of heterozygosity (LOH) is a powerful technique for identifying chromosomal regions that may contain tumour suppressor genes. LOH has been described on chromosome 6 in ovarian carcinoma using restriction fragment length polymorphism analysis with a small number of probes. We studied 29 ovarian carcinomas with 19 probes mapping to chromosome 6. Sixteen of the 29 tumours showed LOH on 6q (55%). Of these 16, 63% showed loss of all informative markers on that arm. One tumour showed loss of 6q24-qter, localising the putative tumour suppressor gene to that region. Loss on 6p was 28% overall. However, using three dinucleotide repeat primer pairs from 6p to study LOH in seven selected tumours, LOH was demonstrated at both 6p22.3-pter and at 6p12-6p22. These results confirm that 6q harbours a tumour suppressor gene of relevance to ovarian carcinoma and suggest that there may also be a similar gene(s) on 6p. By Southern analysis, there was no evidence of genomic rearrangements of the oestrogen receptor gene, located at 6q25.1. LOH on 6q was more common in high than low grade tumours. The relevance of our findings to previous work in ovarian cancer and other solid tumours is discussed.
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PMID:Frequent loss of heterozygosity on chromosome 6 in human ovarian carcinoma. 809 76

Genetic changes have been shown to be important in determining the multistep progression of cancer. Allele loss studies and karyotypic analysis of epithelial ovarian tumours have indicated the presence of putative tumour suppressor genes on chromosomes 6, 11, 13, 17, 18, 22, and X. We have focused on chromosome arm 6q to identify the minimal region that may contain a putative tumour suppressor gene. Nineteen polymorphic microsatellite markers from 6q and one centromeric marker (D6S294) have been used to detect allele loss in 68 ovarian tumours (six benign, six borderline, and 56 with malignant histology). Allele loss was evaluated by separation of fluorescence labelled polymerase chain reaction-amplified products. Forty-six of fifty-six (82%) malignant tumours showed allele loss on 6q, whereas only four of 56 had lost all the markers tested. Forty-one of fifty-six (73%) malignant tumours showed allele loss at 6q26-27. The minimal region of allele loss was between markers D6S264 and D6S297 (3 cM), with maximal allele loss of 62% at D6S193 and 52% at D6S297. Three tumours showed loss of D6S193 only, while retaining flanking informative markers. Allele loss around 6q26-27 was observed in all histological types of epithelial ovarian cancer and did not correlate with any clinical factors. In addition, there was allele loss at ESR (56%) and D6S286 (47%), though a minimal region was not defined. Allele loss at 6q12-25 correlated significantly with endometrioid and mucinous ovarian malignant tumours (P = 0.01). The physical mapping of the region between D6S297 and D6S264 will allow the eventual identification of the putative tumour suppressor gene.
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PMID:Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer. 870 48

Antibodies against the P53 tumour suppressor gene product are present in the serum of many cancer patients, but with varying frequencies ranging from 0 to 30%. Approximately 15-20% of patients with ovarian carcinoma develop auto-antibodies against p53 that circulate in the serum. Since many ovarian cancer patients develop ascites during their disease, we speculated that p53 antigen and/or p53 auto-antibodies may be present in this biological fluid. Ninety-six ascites fluids from women with primary ovarian cancer and one from a patient with cancer of the breast, which metastasised to the ovaries, were analysed for p53 auto-antibodies. Seventeen ascites fluids (18%) contained auto-antibodies. For 30 of these patients, serum was also available. Auto-antibodies were present in both serum and ascites in 6/30 patients; 22 patients were negative in both ascites and serum; and 2 patients had auto-antibodies only in their serum. All 97 ascites fluids were also analysed for p53 antigen and 7 (7%) were positive. None of the 17 p53 auto-antibodies-positive ascites fluids were positive for p53 antigen suggesting that p53 auto-antibodies may interfere with p53 antigen detection by capturing the antigen. In total, 24 patients (25%) had either p53 auto-antibodies or p53 protein in their ascites fluid. These data demonstrate that p53 auto-antibodies and/or p53 protein are present in ascites and may have some value for tumour diagnosis, prognosis or monitoring.
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PMID:Detection of the TP53 tumour suppressor gene product and p53 auto-antibodies in the ascites of women with ovarian cancer. 907 10

This short report describes the detection of mutations of the TP53 tumour suppressor gene in sporadic ovarian carcinomas using archival paraffin-embedded tissues and automated fluorescent DNA sequencing. TP53 mutations were detected in eight tumours. Missense mutations predominated and all were transitions. Mutations were commonest in late-stage serous tumours. In three cases, where tissue was available, the mutations were homogeneous throughout several sections of the bilateral ovarian tumours and in omental metastases. These data confirm the findings of previous investigations describing TP53 mutation in ovarian carcinoma and demonstrate that archival paraffin-embedded tissues can be used for such analyses.
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PMID:TP53 mutation in ovarian carcinoma. 930 56

Ovarian carcinoma is often associated with overexpression of cytokines that may exert autocrine and paracrine growth effects, as well as genetic alterations in (proto)oncogenes and tumour suppressor genes, such as p53. The p53 protein is not only involved in the regulation of cell cycle and apoptosis, it is also involved in the in vitro regulation of IL-6 gene expression. In this study, 30 tumours of patients with a primary diagnosis of human ovarian carcinoma were characterised for p53 expression with immunohistochemistry and analysed for the expression of M-CSF, IL-6, IL-1 beta, IL-11 and TNF-alpha with Northern blotting. Nuclear and cytoplasmic p53 staining was observed in 27% (8/30), cytoplasmic staining in 30% (9/30), and no p53 staining in 43% (13/30) of the tumours. In 70% (21/30) of the tumours, M-CSF mRNA was expressed, in 40% (12/30) TNF-alpha, and in 30% (9/30) IL-6. None of the tumours expressed IL-1 beta or IL-11. The expression of TNF-alpha occurred more frequently in M-CSF positive tumours compared to M-CSF negative tumours (52% (11/21) versus 11% (1/9), P < 0.05). TNF-alpha expression was also associated with better responses to chemotherapy (P < 0.02). M-CSF expression was associated with nuclear p53 staining (P < 0.05). The p53 positive tumours more frequently expressed one or more cytokines (88%) compared with p53 negative tumours (54%, P < 0.05). This study suggests that mutations in the p53 gene might be associated with cytokine overexpression, especially M-CSF.
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PMID:Expression of macrophage colony-stimulating factor (M-CSF), interleukin-6, (IL-6), interleukin-1 beta (IL-1 beta), interleukin-11 (IL-11) and tumour necrosis factor-alpha (TNF-alpha) in p53-characterised human ovarian carcinomas. 947 Aug 14

The role and prognostic value of the tumour suppressor p21/WAF1 expression in epithelial ovarian cancer has not yet been defined. Therefore, the expression of p21/WAF1 was assessed immunohistochemically (IHC) in 316 epithelial ovarian malignancies in relation to p53, cell proliferation and patient survival. p21/WAF1 expression was inversely correlated with p53 and cell proliferation. Low p21/WAF1 expression was significantly associated with high grade of the tumour (P = 0.0005), advanced FIGO stage (P = 0.001) and primary residual tumour (P = 0.0001). Low p21/WAF1 expression was a marker of poor overall survival (P = 0.012). Similarly, p53-positivity and high cell proliferative activity were significant predictors of poor survival in univariate analyses. Moreover, the patients with p21-/p53+ tumours had a poorer overall (P < 0.00005) and recurrence-free (P = 0.0005) survival in univariate analyses, and the p21/p53 expression independently predicted tumour recurrence in Cox's multivariate analysis. Our results suggest that p21/WAF1 expression is mostly p53-dependent in epithelial ovarian cancer. High p21/WAF1 expression seems to function as a negative cell cycle regulator and as a marker of favourable disease outcome in epithelial ovarian cancer. In addition, the patients with their tumour expressing no or low p21/WAF1 protein but positive for p53 had a notably higher risk of recurrent disease, implicating that these patients might be more prone to treatment failures.
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PMID:p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. 1020 7


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