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)

The presence of gemistocytes in low-grade astrocytomas is regarded as a sign of poor prognosis because the majority of gemistocytic astrocytomas rapidly progress to anaplastic astrocytoma or glioblastoma. To elucidate the role of gemistocytes in astrocytoma progression, we assessed the fraction of neoplastic gemistocytes, bcl-2 expression, p53 mutations, p53 immunoreactivity (PAb 1801), and proliferative activity (MIB-1) in 40 low-grade astrocytomas (World Health Organization (WHO) Grade II) with histologically proven progression to anaplastic astrocytoma (WHC Grade III) or glioblastoma (WHO Grade IV). Astrocytoma progression took significantly less time in patients with a low-grade astrocytoma containing more than 5% gemistocytes (35 months) than in those with lesions containing less than 5% gemistocytes (64 months; p = 0.038). All 11 astrocytomas with more than 5% gemistocytes contained a p53 mutation, whereas the incidence of p53 mutations in astrocytomas with less than 5% gemistocytes was 61% (p = 0.017). In low-grade astrocytomas the p53 labeling index (LI) of gemistocytes (7.4%) was significantly higher than in all tumor cells (3.2%, p = 0.0014). Gemistocytes showed a significantly higher bcl-2 expression than all tumor cells, with a mean bcl-2 1 of 15.6% versus 2.7% in low-grade astrocytomas (p = 0.0004), 20.9% versus 3.0% in anaplastic astrocytoma (p = 0.002), and 30.2% versus 5.2% in glioblastomas (p = 0.0002). In contrast, gemistocytes showed a significantly lower proliferating activity than the mean of all tumor cells, with a mean MIB-1 LI of 0.5% versus 2.6% in low-grade astrocytomas, 1.5% versus 11.6% in anaplastic astrocytoma, and 1.7% versus 16.6% in glioblastomas (p < 0.0001). These data show that low-grade astrocytomas with a significant fraction of gemistocytes progress more rapidly and typically carry a p53 mutation. The vast majority of gemistocytes are, however, in a nonproliferative state (G0 phase of the cell cycle), which suggests terminal differentiation. Their accumulation within astrocytomas may be due to bcl-2-mediated escape from apoptosis.
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PMID:Role of gemistocytes in astrocytoma progression. 904 64

Malignant astrocytomas are uncommon brain tumors in children and it is known that astrocytic tumors with similar degrees of histologic anaplasia often show different biologic behaviour. Their uncommon occurrence has resulted in relatively few studies of the molecular biology and genetics of pediatric malignant astrocytomas with somewhat conflicting results, in contrast with the many studies addressing astrocytomas in adults. p53 immunoreactivity has been used to screen tissues for the abnormal presence of the p53 protein and abnormal immunoreactivity has been demonstrated in one-half to two-thirds of adult astrocytomas. We studied the frequency of p53 immunoreactivity and gene alteration in 21 children with malignant astrocytomas (anaplastic astrocytoma and glioblastoma multiforme) and analysed the survival of patients with p53 immunoreactive versus non-reactive tumors. Of the cases examined, 8 were anaplastic astrocytoma (AA) and 13 were glioblastoma multiforme (GM). We found that the overall frequency of p53 immunoreactivity of 47% in this group of pediatric malignant astrocytomas is similar to that reported for adult astrocytomas. The median survival in both p53-positive and p53-negative groups of pediatric malignant astrocytomas was similar: however, the number of deaths in each group and the distribution of p53 scores is not statistically significant. Further studies to precisely identify p53 and other genetic mutations in pediatric gliomas are needed to understand their biology and the rationale for therapeutic options.
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PMID:p53 protein in pediatric malignant astrocytomas: a study of 21 patients. 904 84

As the molecular events responsible for astrocytoma formation and progression are being clarified, it is becoming possible to correlate these alterations with the specific histopathological and biological features of astrocytoma, anaplastic astrocytoma and glioblastoma multiforme. In WHO grade II astrocytomas, autocrine stimulation by the plateletderived growth factor system coupled with inactivation of the p53 gene may lead to a growth stimulus in the face of decreased cell death with slow net growth ensuing. Such cells would also have defective responses to DNA damage and impaired DNA repair, setting the stage for future malignant change. Such biological scenarios recapitulate many of the clinicopathological features of WHO grade II astrocytomas. Anaplastic astrocytomas further display release of a critical cell cycle brake that involves the CDKN2/p16, RB and CDK4 genes. This results in mitoses seen histologically; clinically, there is more conspicuous, rapid growth. Finally, glioblastomas may emerge from the microenvironmental outgrowth of more malignant clones in a complex vicious cycle that involves necrosis, hypoxia, growth factor release, angiogenesis and clonal selection; growth signals mediated by activation of epidermal growth factor receptors may precipitate glioblastomas. It is clear as well that glioblastoma multiforme can arise via a number of independent genetic pathways, although the clinical significance of these distinctions remains unclear.
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PMID:A molecular genetic model of astrocytoma histopathology. 916 27

Alterations of the p53 protein, which is a 53 kD phosphoprotein and gene product of the p53 gene, has been found to play a major role in the genesis of a variety of human malignancies including tumors of the central nervous system. We investigated 50 tumor specimens from primary central nervous system neoplasms. Tissue samples were screened for mutations by the single-strand conformation polymorphism method and detected mutations were sequenced. All tissue specimens were stained immunohistochemically for p53 protein, which when altered accumulates in the nucleus due to prolonged half-life. Mutations were found in six cases, including one pilocytic astrocytoma World Health Organization (WHO) grade I, two astrocytomas WHO grade II, two anaplastic astrocytomas WHO grade III, and one primitive neuroectodermal tumor (PNET). In terms of relative frequency mutations were found mostly in the group of anaplastic astrocytomas WHO grade III. Interestingly, no mutations were found in the group of investigated glioblastomas. P53 immunopositivity did not correlated with the mutations found, whereas the staining index was significantly higher in the cases with detected mutations than in those without. When p53 alterations is seen as an indicator for different pathogenic pathways in glioma formation, this study gives evidence for a difference between anaplastic astrocytoma and glioblastoma. However, since there was a great overlap in p53 immunopositivity and p53 mutation in tumors of different WHO grades and entities, it seems that p53 will not act as a marker molecule neither for tumor entities nor for tumor malignancy.
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PMID:p53 mutation and protein alteration in 50 gliomas. Retrospective study by DNA-sequencing techniques and immunohistochemistry. 922 41

Despite the use of multimodal therapy, higher-grade glioma is still uniformly fatal in the adult population. There is a considerable difference between the length of survival in each given patient, even within the same tumor type and malignancy grade group, suggesting that there are factors that might differentially influence outcome. To identify such factors, 107 patients with anaplastic or malignant glioma were retrospectively investigated. Clinical parameters and paraclinical data on the p53, mdm2, and EGFR genes at the DNA or protein level were evaluated by univariate analysis and Cox proportional hazards regression modeling. Kaplan-Meier survival estimation demonstrated that immunohistochemical positivity for mdm2 protein in patients with anaplastic astrocytoma or with glioblastoma multiforme was associated with a shorter survival time (p = 0.02). P53 gene mutations and immunopositivity for the epidermal growth factor receptor (EGFR) protein were not significantly related to poor prognosis. The Cox proportional hazards model revealed immunohistochemical positivity for p53, mdm2, or for both of them, the presence of postoperative irradiation, and the extent of surgical resection of tumor to be variables significantly associated with prolonged survival. EGFR overexpression, age over 60 years, and Karnofsky performance score below 40 points did not significantly shorten survival time. In conclusion, the present study identified immunohistochemically detected mdm2-protein overexpression as a statistically significant negative prognostic parameter in patients bearing anaplastic or malignant glioma. Association analysis of variables revealed a possible correlation between mdm2 and p53, which is also consistent with the biological interaction mode of both proteins in vivo.
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PMID:Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival. 926 37

Amongst the human astrocytic tumours, the commonest of primary brain tumours, the clinical outcome of astrocytoma (AS) is significantly better than anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Often, low grade tumours can progress to or recur with a more malignant phenotype. Recent loss of heterozygosity (LOH) reports suspect the involvement of a tumour suppressor gene, different from p53, in the 17p13.3 region of the human chromosome. However, the effect of LOH of 17p13.3 region on tumour histology at presentation and prognosis is as yet undefined. As a first step to define the role of this putative oncogene in astrocytic tumour progression, we correlated the LOH of a locus, D17S379, in 17p13.3 region and the p53 locus in 17p13.1 region with the histopathology of astrocytic tumours by PCR based microsatellite and restriction fragment length polymorphism of DNA extracted from microdissected paraffin sections of 45 astrocytic tumours of different histopathological grades. LOH of D17S379 was significantly associated (P=0.02) with AA and GBM (high grade malignancy), while no such preferential association was found with LOH of p53. There were no mutations in the exons 5 to 9 of p53 gene in the five tumours with LOH of D17S379 but not of p53 region. In a case of AA with a heterogenous microscopic appearance, heterozygosity of D17S379 was lost only in the area with a more malignant histology while both areas had no LOH or mutation of p53. A locus at the 17p13.3 region, independent of the p53 locus, is involved in a large subset of astrocytic tumours during transformation into a more malignant phenotype, and thus may be a link in the chain of genetic events occurring in astrocytic tumour progression.
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PMID:Loss of heterozygosity of a locus on 17p13.3, independent of p53, is associated with higher grades of astrocytic tumours. 926 74

Primary glioblastomas develop rapidly de novo through a genetic pathway characterized by amplification/overexpression of EGFR and of MDM2 genes. Secondary glioblastomas develop more slowly through progression from low grade or anaplastic astrocytoma and show a high incidence of a p53 mutation. In the present study, primary and secondary glioblastomas were analyzed for p16 deletions and CDK4 amplification by differential PCR and for loss of expression of the retinoblastoma (RB) gene by immunohistochemistry. Except for one case, alterations in the structure or expression of p16, CDK4 and RB were mutually exclusive. The overall incidence of aberrant expression of these genes coding for components of the cell-cycling-regulatory system was similar in primary (14/28; 50%) and secondary glioblastomas (9/23; 39%). However, p16 deletions were significantly more frequent in the former (10/28; 36%) than in the latter (1/23, 4%; P = 0.0075), suggesting that this alteration constitutes an additional genetic hallmark of the primary (de novo) glioblastoma.
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PMID:Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. 934 29

A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma.
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PMID:Biology and treatment of malignant glioma. 950 24

Astrocytomas are the most common tumors of the central nervous system (CNS). Their malignant counterparts, anaplastic astrocytoma and glioblastoma, are lethal neoplasms with poor clinical outcome and they frequently carry mutations of TP53 tumor suppressor gene. In order to determine the frequency and type of this molecular alteration in the Polish population, we analyzed the polymerase chain reaction products corresponding to the most conservative exons 5-8 for single-strand conformation polymorphism and confirmed the presence of mutations by direct DNA sequencing. We identified mutations in one of five (20%) anaplastic astrocytomas and in eight of 28 (29%) glioblastomas; the mutations were most frequently identified in the exon 8 (six glioblastomas). The frequency of TP53 mutations is thus similar to the corresponding data from other studies, and the type of mutations suggests the participation of endogenous etiological factor.
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PMID:TP53 mutations in malignant astrocytomas. 952 27

Glioblastomas may develop rapidly without clinical and histopathological evidence of a less malignant precursor lesion (de novo or primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas typically show overexpression of EGFR, but rarely p53 mutations, while secondary glioblastomas frequently carry a p53 mutation, but usually lack overexpression of EGFR, suggesting that these glioblastoma subtypes develop through distinct genetic pathways. In the present study, we assessed the expression of Fas/APO-1 (CD95), an apoptosis-mediating cell membrane protein, and its relation to necrosis phenotype in primary and secondary glioblastomas. Large areas of ischemic necroses were observed in all 18 primary glioblastomas, but were significantly less frequent in secondary glioblastomas (10 of 19, 53%; p = 0.0004). Fas expression was predominantly observed in glioma cells surrounding large areas of necrosis and was thus significantly more frequent in primary glioblastomas (18 of 18, 100%) than in secondary glioblastomas (4 of 19, 21%; p < 0.0001), suggesting that these clinically and genetically defined subtypes of glioblastoma differ in the extent and mechanism of necrogenesis. Necrosis and microvascular proliferation are histologic hallmarks of the glioblastoma. Following incubation of glioblastoma cell lines under hypoxic/anoxic conditions for 24-48 hours, Fas mRNA levels remained unchanged, whereas VEGF expression was markedly upregulated. This suggests that in contrast to VEGF Fas expression is not induced by ischemia/hypoxia. Analysis of Fas mRNA levels in a glioblastoma cell line containing a p53 mutation and an inducible wild-type p53 gene showed little difference under induced and noninduced conditions, suggesting that in glioblastomas, Fas expression is not directly linked to the p53 status.
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PMID:Necrogenesis and Fas/APO-1 (CD95) expression in primary (de novo) and secondary glioblastomas. 960 Feb 16


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