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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant astrocytoma, the most prevalent primary brain tumor, is resistant to all known therapies and frequently harbors mutations that inactivate p53 and activate Ras signaling. We have generated mouse strains that lack p53 and harbor a conditional allele of the NF1 tumor suppressor that negatively regulates Ras signaling. The mice develop malignant astrocytomas with complete penetrance. The majority of tumors display characteristics of glioblastoma multiforme with concomitant alteration of signaling pathways previously described in the human counterparts of this neoplasm. We find that the sequence of tumor suppressor inactivation influences tumorigenicity and that earliest evidence of tumor formation localizes to regions of the brain that contain a multipotent stem cell population capable of in vivo differentiation into neurons and glia.
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PMID:Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. 1609 65

Little is known about the cellular and genetic changes that occur in human astrocytomas following radiation therapy (RT). Experimental studies would suggest that early effects include induction of p53 and p21 expression, cell cycle arrest, and selection of tumor cells with molecular changes that correlate with radiation resistance. Unfortunately, tissue sampling of primary human astrocytomas closely following radiation therapy is uncommon, hindering comparative assessment of primary human tumors. Through local databases, we were able to collect eight cases in which tissue was resected within 8 weeks of RT because of bulky residual disease: two patients with grade II diffuse astrocytomas (LGA) and 6 patients with high-grade astrocytomas (HGA; 1 anaplastic astrocytoma, 5 glioblastomas). Routine histopathologic sections, MIB-1 labeling index (LI), p53 and p21 expression, and EGFR expression were compared between the pre- and post-RT samples. Only one tumor (52d post-RT) showed prominent radiation-induced histopathologic changes. p53 expression was detected in two tumors pre-RT and in six tumors post-RT. In the four tumors in which p53 expression was induced, the post-RT LI was lower in each case, and p21 expression had increased in 3/4 of these cases. No change in LI was detected in tumors in which p53 expression was unchanged. EGFR expression was not altered following RT. The results of this unique series document that some primary human astrocytomas increase expression of p53 and p21 and decrease proliferation in response to RT. However, the small size of the series argues for further studies of radiation induced molecular changes in primary human astrocytoma tissue.
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PMID:Alterations in p53, p21, and MIB-1 labeling index in primary human astrocytomas following radiation therapy. 1619 85

In population-based glioma patients, we examined survival in relation to potentially pertinent constitutive polymorphisms, serologic factors, and tumor genetic and protein alterations in epidermal growth factor receptor (EGFR), MDM2, and TP53. Subjects were newly diagnosed adults residing in the San Francisco Bay Surveillance Epidemiology and End Results Area during 1991 to 1994 and 1997 to 1999 with central neuropathology review (n = 873). Subjects provided blood for serologic studies of IgE and IgG to four herpes viruses and constitutive specimens for genotyping 22 polymorphisms in 13 genes (n = 471). We obtained 595 of 697 astrocytic tumors for marker studies. We determined treatments, vital status, and other factors using registry, interview, medical record, and active follow-up data. Cox regressions for survival were adjusted for age, gender, ethnicity, study series, resection versus biopsy only, radiation, and chemotherapy. Using a stringent P < 0.001, glioma survival was associated with ERCC1 C8092A [hazard ratio (HR), 0.72; 95% confidence limits (95% CL), 0.60-0.86; P = 0.0004] and GSTT1 deletion (HR, 1.64; 95% CL, 1.25-2.16; P = 0.0004); glioblastoma patients with elevated IgE had 9 months longer survival than those with normal or borderline IgE levels (HR, 0.62; 95% CL, 0.47-0.82; P = 0.0007), and EGFR expression in anaplastic astrocytoma was associated with nearly 3-fold poorer survival (HR, 2.97; 95% CL, 1.70-5.19; P = 0.0001). Based on our and others' findings, we recommend further studies to (a) understand relationships of elevated IgE levels and other immunologic factors with improved glioblastoma survival potentially relevant to immunologic therapies and (b) determine which inherited ERCC1 variants or other variants in the 19q13.3 region influence survival. We also suggest that tumor EGFR expression be incorporated into clinical evaluation of anaplastic astrocytoma patients.
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PMID:Serum IgE, tumor epidermal growth factor receptor expression, and inherited polymorphisms associated with glioma survival. 1661 82

The molecular basis for alternative lengthening of telomeres (ALT), a prognostic marker for glioma patients, remains unknown. We examined TP53 status in relation to telomere maintenance mechanism (TMM) in 108 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma from New Zealand and United Kingdom. Tumor samples were analyzed with respect to telomerase activity, telomere length, and ALT-associated promyelocytic leukemia nuclear bodies to determine their TMM. TP53 mutation was analyzed by direct sequencing of coding exons 2 to 11. We found an association between TP53 mutation and ALT mechanism and between wild-type TP53 and telomerase and absence of a known TMM (P < 0.0001). We suggest that TP53 deficiency plays a permissive role in the activation of ALT.
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PMID:Association of mutant TP53 with alternative lengthening of telomeres and favorable prognosis in glioma. 1681 15

Malignant gliomas may manifest at any age including congenital and childhood cases. Peak incidence is, however, in adults older than 40 years. Males are more frequently affected than females. The sole unequivocal risk factor is therapeutic ionizing irradiation. Malignant gliomas comprise a spectrum of different tumor subtypes. Within this spectrum, glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglioma share as basic features preferential location in cerebral hemispheres, diffuse infiltration of brain tissue, fast tumor growth with fatal outcome within months or years. Invasion is regarded as one of the main reasons for poor therapeutic success, because it makes complete surgical removal of gliomas impossible. Invasion of glioma cells requires interaction with the extracellular matrix and with surrounding cells of the healthy brain tissue. Vascular proliferates and tissue necrosis are characteristic features of malignant gliomas, in particular glioblastoma. These features are most likely the consequence of rapidly increasing tumor mass that is inadequately oxygenized by the preexisting vasculature. In malignant glioma, distinct molecular pathways including the p53 pathway, the RB pathway and the EGFR pathway show frequent alterations that seem to be pathogenetically relevant. Methylguanine-methyltransferase (MGMT) promoter methylation status in glioblastoma and 1p19q deletion status in anaplastic oligodendroglioma are associated with response to chemotherapy. The role of neuropathology and neurobiology in neurooncology is 1. to provide a clinically meaningful classification of brain tumors on basis of pathobiological factors, 2. to clarify etiology and pathogenesis of brain tumors as rational basis for development of new diagnostic tests and therapies, and 3. to translate testing for new clinically relevant molecular parameters into clinical application.
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PMID:Malignant glioma: neuropathology and neurobiology. 1694 63

Pleomorphic xanthoastrocytoma (PXA) is a rare primary low-grade astrocytic tumor, recently classified as a neuroglial tumor. It generally occurs in children and young adults and shows benign behaviour (WHO II), although an anaplastic variant and malignant potential have been described. Pleomorphic xanthoastrocytomas with malignant transformation have been reported in three out of eight patients operated on for this type of tumor in our department in the last 15 years. The three patients were two adult women and a child, the primary tumors were located in the cortex of the right temporal lobe, and treatment consisted of complete surgical resection. Histological examination revealed simple PXA in two patients and a PXA with anaplastic foci in the other. Mean recurrence time was 5.7 years, with the original xanthoastrocytoma evolving to glioblastoma in two cases and anaplastic astrocytoma in the third. All three patients underwent a second operation, followed by adjuvant therapies. Two died from tumor progression and one from brain edema after intracerebral haemorrhage. A review of the available PXA literature dating back to 1979 revealed 16 cases of primary anaplastic astrocytoma and 21 cases of PXA with malignant transformation. Our experience adds three more cases of malignant transformations, outlining once again the potential malignancy of pleomorphic xanthoastrocytomas and the fact that prognosis in these cases is the same as for primary anaplastic astrocytoma and glioblastoma. Analysis of glioneuronal markers, Ki67 and p53 in all pleomorphic xanthoastrocytomas did not prove to be a discriminating factor to identify a subgroup of xanthoastrocytomas prone to malignancy. Accordingly, these tumors demand close long-term clinical and radiological follow-up.
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PMID:Malignant progression in pleomorphic xanthoastrocytoma: personal experience and review of the literature. 1718 43

Glioblastoma multiforme (GBM) develops from astrocytes and is the most aggressive primary cancer in humans. Invading cells grow rapidly and form their own blood vessels making them difficult to surgically remove or treat. GBM may develop de novo (primary) or through progression from a low-grade or anaplastic astrocytoma (secondary). Mutational inactivation of the p53 gene and presence of aberrant p53 expression are reported in GBM, suggesting that p53 has a role in tumor progression. This study of seven de novo GBM and four secondary GBM patients, indicated that nine out of eleven (82%) had overexpression of p53. Our histopathological analysis showed that the expression of p53 in three out of four (75%) secondary GBM was confined to the nucleus and the p53 positive cells were randomly distributed throughout the tumor. The expression of p53 in four out of seven (57%) de novo GBM was cytoplasmic, diffusive, and confined to the perivascular region of the tumor. In two (29%) de novo samples both nuclear as well as cytoplasmic staining that was not confined to the perivascular area was observed. The results suggest that cytoplasmic p53 may contribute to the formation and maintenance of de novo GBM by virtue of its control of the vasculature of tumors. Furthermore, cytoplasmic p53 may reflect an association of p53 with Cullin 7, PARC, or with the sequestering partner of p53, mortalin. These results underscore the significance of p53 in the tumorigenesis of de novo GBM.
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PMID:Revisiting the role of p53 in primary and secondary glioblastomas. 1721 19

Astrocytomas are the most common pediatric brain tumors, accounting for 7%-8% of all childhood cancers. Relatively few studies have been performed on their molecular properties; therefore, classification of pediatric astrocytic tumors into genetic subtypes similar to that of adult tumors remains to be defined. Here, we report an extensive characterization of 44 pediatric astrocytomas--16 diffuse astrocytomas (WHO grade II), 10 anaplastic astrocytomas (WHO grade III), and 18 glioblastomas (WHO grade IV)--in terms of genetic alterations frequently observed in adult astrocytomas. Some form of p53 mutation was found in three diffuse astrocytomas, in three anaplastic astrocytomas, and in six glioblastomas examined; PTEN mutations were detected only in two glioblastomas. EGFR amplification was detected in only one anaplastic astrocytoma and two glioblastomas, but no amplification was observed for the PDGFR-alpha gene. Loss of heterozygosity (LOH) on 1p/19q and 10p/10q was less common in pediatric astrocytic tumors than in those seen in adults, but the frequency of LOH on 22q was comparable, occurring in 44% of diffuse astrocytomas, 40% of anaplastic astrocytomas, and 61% of glioblastomas. Interestingly, a higher frequency of p53 mutations and LOH on 19q and 22q in tumors from children six or more years of age at diagnosis was found, compared with those from younger children. Our results suggest some differences in children compared to adults in the genetic pathways leading to the formation of de novo astrocytic tumors. In addition, this study suggests potentially distinct developmental pathways in younger versus older children.
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PMID:Molecular pathogenesis of pediatric astrocytic tumors. 1732 74

Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.
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PMID:Genetic pathways to primary and secondary glioblastoma. 1745 51

The authors present the case of a 51-year-old man who presented with an anaplastic astrocytoma and anaplastic oligodendroglioma that developed 6 years after subtotal resection of a central neurocytoma in his right lateral ventricle. He had received neither radiation therapy nor chemotherapy after the original resection. On readmission, neuroimaging revealed a mass in the right parietal lobe and a diffuse lesion in the right temporal lobe, insula, and corona radiata. Because both lesions extended to the right lateral ventricle wall, they were regarded as recurrent rather than metachronous tumors. Histological examination revealed anaplastic oligodendroglioma in the parietal lobe and anaplastic astrocytoma in the insula. One year later, the anaplastic astrocytoma was found to have transformed into a glioblastoma multiforme. Fluorescence in situ hybridization analysis and immunohistochemical examinations detected deletions of the lp36 and 19q13 loci, and nuclear accumulation of TP53 protein in the anaplastic oligodendroglioma but not in the glioblastoma multiforme. These findings suggest that central neurocytoma or progenitor cells have the potential for oligodendrocytic and astrocytic transformation with different genetic aberrations.
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PMID:Anaplastic astrocytoma and anaplastic oligodendroglioma occurring 6 years after subtotal resection of a central neurocytoma. Case report. 1763 93


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