Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant peripheral nerve sheath tumors (MPNST) are highly malignant sarcomas arising either de novo or in transition from neurofibroma. Although relatively little is known of the molecular genetic alterations that underlie their formation, recent DNA sequencing studies have demonstrated the presence of p53 mutations in some MPNST. This tumor-suppressor gene has been implicated in the progression of a variety of human malignancies, including sarcomas. Employing the anti-p53 monoclonal antibody Do-7, this retrospective immunohistochemical study of p53 gene overexpression in MPNST found reactivity to be present in 68% and to be significant in degree in 57%. In contrast, although some degree of p53 overexpression was present in 48% of neurofibromas, none stained strongly and only 1 of the 27 (4%), a cellular example, showed significant staining. No difference in the frequency or degree of p53 staining was noted between MPNSTs from patients with or without neurofibromatosis 1. The observed overexpression of the gene product, possibly the reflection of a p53 gene mutation, suggests a role for p53 in the progression of neurofibroma to MPNST. Although the prognostic of p53 overexpression in MPNST remains to be confirmed, in the present series immunopositive tumors were associated with a shorter median patient survival (18 months) than were tumors showing no reactivity (82 months) (P = .02).
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PMID:p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors. 881 80

Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon soft tissue tumors. In children with neurofibromatosis 1 (NF1), a MPNST often arises in a pre-existing neurofibroma, or may represent an initial manifestation without other obvious stigmata of the disease. The development of MPNSTs may be associated with instability of the p53 tumor suppressor gene since it is the most frequent genetic abnormality in soft tissue sarcomas. To assess the presence of p53 accumulation in MPNSTs and its correlation with clinical and pathologic features, we studied 12 neurofibromas (NFs), including 4 tumors with cellular features (one congenital) and 10 MPNSTs. Six MPNSTs were associated with NF1, all of which developed within a plexiform neurofibroma. Cell proliferation evaluated with an antibody to Ki-67 and nuclear p53 staining were both detected by immunohistochemistry. We found p53 positivity in 60% of MPNSTs. All NFs except the congenital tumor were p53 immunonegative (P < 0.01). Rare p53-positive nuclei were detected in the transitional zone in two of six MPNSTs arising in plexiform NFs. Ki-67 distinguished the NFs from MPNSTs (P < 0.005). Half of the NF1 patients with p53-positive MPNSTs developed recurrence or metastases or developed a second malignancy within 2 years of diagnosis, whereas patients with p53-positive sporadic MPNSTs were free of disease 1 to 7 years later. We found p53 accumulation more frequently in NF1-associated MPNSTs. p53 mutations may be an additional biologic factor to account for the poor prognosis in these tumors.
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PMID:p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant peripheral nerve sheath tumors in children. 1034 83

Triton tumors are rare variants of malignant peripheral nerve sheath tumor (MPNST) with muscle differentiation, often seen in patients with neurofibromatosis 1 (NF1). Individuals affected with NF1 harbor mutations in the NF1 tumor suppressor gene and develop neurofibromas and MPNSTs. The NF1 gene is expressed in Schwann cells and its expression is lost in schwannian neoplasms, suggesting a role in malignant development. Separately, there is evidence that p53 suppressor gene mutations are involved in MPNSTs. To determine the role of the NF1 and p53 genes in the development of the malignant Triton tumor we examined 2 such tumors, 1 from a 3-year-old boy without clinical manifestations of NF1 and another from a 24-year-old man with NF1. Histological analysis of these tumors showed both neural and muscle differentiation with S-100 and desmin immunoreactivity, respectively. Reverse transcribed RNA polymerase chain reaction (RT-PCR) of NF1 mRNA showed NF1 expression in the sporadic tumor. Strong nuclear immunoreactivity for p53 was observed throughout the malignant population in both tumors. This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors. The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.
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PMID:Molecular analysis of malignant triton tumors. 1045 14

Canine cancer is of major significance in terms of animal health and welfare and soft tissue sarcomas are an important group of tumours accounting for approximately 15% of all canine tumours presented. Abnormal p53 protein expression and gene mutations have been identified in a number of different canine tumour types. However, mdm2 gene amplification has only been investigated in a limited number of canine osteosarcomas. In this present study a series of canine soft-tissue sarcomas (STS) were examined for p53 mutations and/or mdm2 amplification. For p53 mutational studies polymerase chain reaction and direct DNA sequencing was used. Gene mutations were identified in 6 of 30 (20%) primary tumour cases including MPNST (n=3) leiomysarcoma (n=1), heamangiosarcoma (n=1) and sarcoma (n=1). mdm2 gene amplification was assessed by Southern Blot. Although there was no evidence for major gene rearrangements, gene amplification was detected in 4 of 35 (11.4 %) primary tumours including MPNST (n=2), rhabdomyosarcoma (n=2). A total of 33 cases were examined for both p53 mutations and mdm2 amplification. Seven of the tumours were positive for p53 mutations, while five were positive for mdm2 amplification. With the exception of one case, a reciprocal relationship between the presence of a p53 mutation and mdm2 gene amplification was demonstrated.
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PMID:Analysis of p53 mutational events and MDM2 amplification in canine soft-tissue sarcomas. 1167 55

This study investigates differences in expression of the cell cycle/growth activation markers p53, p16, and p27, and their relationship with nerve sheath cell and proliferation markers among plexiform neurofibromas (PNF), NF1-related and non-NF1 MPNSTs of different histologic grades and between benign-appearing and malignant areas in the MPNSTs associated with PNFs. Formalin-fixed, paraffin-embedded archival tissue from PNFs and MPNSTs were immunostained using the avidin-biotin-complex method with antibodies to S-100 protein (S-100), Leu7 (CD57), CD34, p16, p27, p53, Mib-1, and topoisomerase II-alpha (TopoIIalpha), with appropriate controls. All PNFs and most low-grade MPNSTs displayed diffuse or focal reactivity for S-100, Leu7, CD34, p16, and p27 and negative reactivity for p53, Mib-1, and TopoIIalpha. Most high-grade MPNSTs displayed decreased or negative reactivity to S-100, Leu7, CD34, p16, and p27 but increased reactivity to p53 (59%), Mib-1 (72%), and TopoIIalpha (72%). In addition, combined nuclear and cytoplasmic (nucleocytoplasmic) p27 staining, which was not seen in the PNF or low-grade MPNST, was observed in 33% of high-grade MPNSTs. These findings suggest that p53, p16, and p27 may be involved in tumor progression in the PNF-MPNST sequence. However, alterations in p53, p16, and p27 do not distinguish between low-grade MPNST and PNF, including PNF adjacent to high-grade MPNST. Although p53, p16, and p27 are unlikely to be reliable markers for early detection of tumor progression in MPNST, p53 reactivity was more frequent in NF1-associated high-grade MPNST and appeared to be a marker for high tumor grade. Combining immunohistochemical stains with histologic grading with careful examination of mitotic activity may provide insight into the progression of peripheral nerve sheath tumors.
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PMID:Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. 1450 95

Neurofibromatosis type 1 (NF1) patients have an 8-13% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNST) which have a very poor prognosis. In this study, cells from eight MPNSTs (six primary and two recurrences) of six clinically and genetically well-characterized NF1 patients were taken into culture. Tracing of loss of heterozygosity (LOH) of the NF1, p53, and p16 gene regions or of abnormal karyotypes enabled identification of tumor cells from five MPNSTs. In two other MPNST-derived cell cultures, LOH of the relevant regions in the original tumors could not be detected, indicating that the obtained cells were nonneoplastic cells. Cells from most MPNSTs grew only under standard culture conditions but not under conditions optimized for Schwann cells. These cells were S100-negative and did not exhibit spindle shape which is a characteristic of Schwann cells. Drastically increased proliferation rates were found for most of the MPNST cells in comparison to Schwann cells derived from benign neurofibromas. Our study demonstrates that genetic analysis is effective and essential for verification of MPNST tumor cells in culture. These verified MPNST cells are valuable for further investigations of the biology and pathogenesis of this malignancy as well as for in vitro pharmacologic studies essential for the development of new therapies.
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PMID:Genetic and phenotypic characterization of tumor cells derived from malignant peripheral nerve sheath tumors of neurofibromatosis type 1 patients. 1520 65

Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14(Arf), and p16(INK4a) proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100beta protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool.
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PMID:Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. 1651 May 76

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n = 37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor alpha and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients.
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PMID:EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy. 1865 Apr 88

Malignant peripheral nerve sheath tumours (MPNSTs) are highly malignant and resistant. Transformation might implicate up regulation of epidermal growth factor receptor (EGFR). Fifty-two MPNST samples were studied for EGFR, Ki-67, p53, and survivin expression by immunohistochemistry and for EGFR amplification by in situ hybridization. Results were correlated with clinical data. EGFR RNA was also quantified by RT-PCR in 20 other MPNSTs and 14 dermal neurofibromas. Half of the patients had a neurofibromatosis type 1 (NF1). EGFR expression, detected in 86% of MPNSTs, was more frequent in NF1 specimens and closely associated with high-grade and p53-positive areas. MPNSTs expressed more EGFR transcripts than neurofibromas. No amplification of EGFR locus was observed. NF1 status was the only prognostic factor in multivariate analysis, with median survivals of 18 and 43 months for patients with or without NF1. Finally, EGFR might become a new target for MPNSTs treatment, especially in NF1-associated MPNSTs.
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PMID:Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs. 1876 52

The purpose of this study was to identify new prognostic biomarkers with clinical impact in malignant peripheral nerve sheath tumor (MPNST), a highly aggressive malignancy for which no consensus therapy exists besides surgery. We have used tissue microarrays (TMAs) to assess in situ expression of 14 cell-cycle-regulating proteins in 64 well-characterized MPNST patients: 36 sporadic and 28 with neurofibromatosis type 1 (NF1). We developed a new software application for evaluation and logistics of the TMA images and performed a literature survey of cell cycle proteins in MPNST. For NF1-associated patients, there was a clear association between nuclear expression of p53 and poor survival (p = 0.004). Among the other proteins analyzed, we also found significant associations between survival and clinical variables, but none were as strong as that for p53. For the total series of MPNSTs, p53 was shown to be an independent predictor of survival, and patients without remission, with tumor size larger than 8 cm, and with positive p53 expression had a 60 times greater risk of dying within the first 5 years compared with the remaining patients (p = 0.000002). This is the most comprehensive study of in situ protein expression in MPNST so far, and expressed p53 was found to be a strong surrogate marker for outcome. Patients in complete remission with a primary p53-positive MPNST diagnosis may be considered in a high-risk subgroup and candidates for adjuvant treatment.
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PMID:Identification of p53 as a strong predictor of survival for patients with malignant peripheral nerve sheath tumors. 1918 48


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