Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Loss of heterozygosity (LOH) on chromosome 10 is the most frequent genetic alteration associated with the evolution of malignant astrocytic tumors and it may involve several loci. The tumor suppressor gene PTEN (MMAC1) on chromosome 10q23 is mutated in approximately 30% of glioblastomas (WHO Grade IV). In this study, we assessed the frequency of PTEN mutations in primary glioblastomas, which developed clinically de novo, and in secondary glioblastomas, which evolved from low-grade (WHO Grade II) or anaplastic astrocytomas (WHO Grade III). Nine of 28 (32%) primary glioblastomas contained a PTEN mutation and an additional case showed a homozygous PTEN deletion. This indicates that after overexpression/amplification of the EGF receptor, loss of PTEN function is the most common alteration in primary glioblastomas. In this series, 5 of 28 (18%) primary glioblastomas showed both a PTEN mutation and EGFR amplification. In contrast, only 1 of 25 (4%) secondary glioblastomas contained a PTEN mutation, and none of them showed a homozygous PTEN deletion. The secondary glioblastoma with a PTEN mutation developed from an anaplastic astrocytoma that already carried the mutation. The observation that secondary glioblastomas have a p53 mutation as a genetic hallmark but rarely contain a PTEN mutation supports the concept that primary and secondary glioblastomas develop differently on a genetic level.
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PMID:PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. 969 Jun 72

Mutations of the p53 tumor suppressor gene are a genetic hallmark of human astrocytic neoplasms, but their predictive role in glioma progression is still poorly understood. We analyzed 144 biopsies from 67 patients with recurrent astrocytoma by single-strand conformation polymorphism and direct DNA sequencing. We found that 46 of 67 patients (69%) had a p53 mutation in at least one biopsy. In 41 of these (89%), the mutation was already present in the first biopsy, indicating that p53 mutations are early events in the evolution of diffuse astrocytomas. Double mutations of the p53 gene were observed in three tumors and also present from the first biopsy. Of 28 low-grade astrocytomas with a p53 mutation, 7 (25%) showed loss of the normal allele in the first biopsy. The allele status remained the same in 95% of the cases, irrespective of whether the recurrent lesion had the same or a higher grade of malignancy. Progression of low-grade astrocytomas to anaplastic astrocytoma or glioblastoma occurred at a similar frequency in lesions with (79%) and without (63%) p53 mutations (P = 0.32), indicating that this genetic alteration is associated with tumor recurrence but not predictive of progression to a more malignant phenotype. However, the time interval until progression was shorter in patients with low-grade astrocytomas carrying a p53 mutation (P = 0.055).
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PMID:Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. 981 15

Abnormal p53 as revealed by immunostaining has been shown to be a predictor of poor outcome in a variety of malignant tumors. This study examines the relationship of p53 immunostaining and survival in 182 adult patients with gliomas. Tumor tissues obtained from patients with glioma within 4 months of initial diagnosis were investigated by immunohistochemical analysis for detection of p53 protein abnormalities using the monoclonal antibody PAb 1801. There were 122 patients with glioblastoma multiforme, 48 patients with anaplastic glioma, and 12 patients with low-grade glioma. Among these patients, 73 of those with glioblastoma multiforme, 35 with anaplastic glioma, and 6 with low-grade glioma had positive p53 immunoreactivity. Kaplan-Meier survival plots (log rank test) showed that the patients with anaplastic astrocytoma or low-grade glioma and p53-positive tumors had longer survival times compared to the patients with p53-negative tumors. No differences in survival were detected among the glioblastoma patients. Cox proportional hazards regression analysis, adjusted for age at diagnosis, showed that the p53 positivity was a significant predictor of longer survival (relative risk = 0.56; 95% confidence intervals = 0.35, 0.90; P = 0. 015) in anaplastic astrocytoma patients, but not in glioblastoma patients (relative risk = 1.03; 95% confidence intervals = 0.82, 1. 29; P = 0.80). These results suggest that anaplastic glioma patients with p53 protein alterations may have a better response to chemoradiation, possibly because the malignant cells cannot arrest in G1 to correct lethal damage induced by chemotherapy or radiotherapy.
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PMID:Prognostic significance of p53 immunoreactivity in patients with glioma. 981 64

Germline p53 mutations carry an increased risk of development of breast cancer, soft tissue and osteosarcomas, brain tumors, leukemia and adrenocortical carcinomas. Cerebral neoplasms are usually of astrocytic lineage and occur in 40% of affected families. This report presents clinical, neuropathological and molecular genetic data from 2 families in France with an identical p53 germline mutation in codon 248 (CGG->TGG; Arg->Trp) and a clustering of CNS tumors. The youngest patient in each family developed a malignant choroid plexus tumor while several young adults of both kindred succumbed to low-grade astrocytoma, anaplastic astrocytoma or glioblastoma. The only non-neural neoplasm was an adrenocortical carcinoma in a boy aged 4 years who developed an anaplastic choroid plexus papilloma 2 years later. Of 2 previously reported inherited choroid plexus tumors, 1 occurred in a family which also carried a germline mutation in codon 248. It remains to be shown whether this unusual pattern of CNS tumors is due to an organ-specific effect of this particular p53 mutation or whether it reflects the genetic background of the affected families.
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PMID:Astrocytomas and choroid plexus tumors in two families with identical p53 germline mutations. 982 43

Twenty-five human gliomas of different histological grade and type were studied for p53 expression by immunohistochemistry and for apoptosis using ApopTag method. p53 expression (percentage of positive cells) was highest in anaplastic astrocytomas, followed by low grade astrocytomas and surprisingly in glioblastomas. Granular cytoplasmic p53 positivity appeared in 4/5 low grade oligodendroglioma and in 2/5 low grade mixed oligoastrocytomas. The means of apoptosis index in the different tumor types ranged between 0.8 and 11.5 with the highest values in anaplastic astrocytoma and glioblastomas. Although the number of cases per group were relatively low and the individual vales showed differences it seems that p53 expression is related to the biological aggressiveness of gliomas. It is also suggested that high level of apoptosis in malignant glioma could represent a p53 independent pathway.
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PMID:Apoptosis and p53 expression in human gliomas. 988 56

Astrocytic tumors occasionally arise in the central nervous system following radiotherapy. It is not clear if these gliomas represent a unique molecular genetic subset. We identified nine cases in which an astrocytoma arose within ports of previous radiation therapy, with total doses ranging from 2400 to 5500 cGy. Irradiated primary lesions included craniopharyngioma, pituitary adenoma, Hodgkin's lymphoma, ependymoma, pineal neoplasm, rhabdomyosarcoma, and three cases of lymphoblastic malignancies. Patients ranged from 9 to 60 years of age and developed secondary tumors 5 to 23 years after radiotherapy. The 9 postradiation neoplasms presented as either anaplastic astrocytoma (3 cases) or glioblastoma multiforme (6 cases). Two of the latter contained malignant mesenchymal components. We performed DNA sequence analysis, differential polymerase chain reaction (PCR), and quantitative PCR on DNA from formalin-fixed, paraffin-embedded tumors to evaluate possible alterations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes. By quantitative PCR, we found EGFR gene amplification in 2 of 8 tumors. One of these demonstrated strong immunoreactivity for EGFR. Quantitative PCR showed chromosome 9p deletions including p16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7). Five of 9 tumors demonstrated diffuse nuclear immunoreactivity for p53 protein. Sequencing of the p53 gene in these 9 cases revealed a mutation in only one of these cases, a G-to-A substitution in codon 285 (exon 8). Somewhat unexpectedly, no mutations were identified in PTEN, a commonly altered tumor suppressor gene in de novo glioblastoma multiformes. Unlike some radiation-induced tumors, no activating point mutations of the K-ras proto-oncogene or base pair deletions of tumor suppressor genes were noted. These radiation-induced tumors are distinctive in their high histological grade at clinical presentation. The spectrum of molecular genetic alterations appears to be similar to that described in spontaneous high grade astrocytomas, especially those of the de novo type.
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PMID:Molecular genetic alterations in radiation-induced astrocytomas. 1032 96

Low-grade diffuse astrocytomas have an intrinsic tendency for malignant progression but the factors determining the kinetics of this process are still poorly understood. We report here the case of a male patient who developed a fibrillary astrocytoma at the age of 33 years and who underwent six surgical interventions over a period of 17 years without radiotherapy or chemotherapy. The first three biopsies spanned a period of 11 years and led to the diagnosis of low-grade, diffuse astrocytoma (WHO grade II), with a growth fraction (MIB-1 labeling index) of 2.3-3.7%. The fourth to sixth biopsies showed histological features of anaplastic astrocytoma (WHO grade III), with growth fractions between 5.0 and 10.5%. The fraction of gemistocytic neoplastic astrocytes also increased, from 0.3% in the first biopsy to 17.5% in the last biopsy and preceded the increase in proliferative activity and transition to anaplastic astrocytoma. The fraction of tumor cells immunoreactive to BCL-2 increased from 0.3% to 8.2%. A p53 mutation in codon 273 (CGT-->TGT, Arg-->Cys) was identified in the first biopsy and persisted throughout the course of the disease. However, the fraction of cells with p53 protein accumulation increased significantly during progression, from 3.2% in the first biopsy to 13.7% in the last. The absence of additional genetic alterations (PTEN mutations, loss of chromosome 10 and 19q) may be responsible for the slow progression and lack of glioblastoma features even after a 17-year disease duration.
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PMID:A case history of glioma progression. 1033 92

We established two glioma cell lines from two surgical specimens obtained at different times from the same patient. One (No. 9R), which was derived from the recurrent tumor (glioblastoma, grade IV), proliferated more rapidly in vitro than the other (No. 9) from the primary tumor (slightly anaplastic astrocytoma, grade II-III). No. 9R showed heterotransplantability in nude mice, whereas No. 9 did not. These findings indicate that No. 9R has a more aggressive or malignant nature than No. 9. Both cell lines showed homozygous deletion of the representative tumor suppressor p16 and p15 genes, but no p53 gene alteration. However, examination of the overall mRNA expression profile using a commercially available cDNA-spotted membrane revealed much higher expression levels of several mRNAs, at least, in No. 9R than in No. 9, although the relationship between these mRNAs and the growth potentials remained unknown. These two cell lines, derived from the same individual, with different proliferating potentials may be useful for studies on the molecular bases of glioma malignancy and progression.
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PMID:Establishment of two glioma cell lines from two surgical specimens obtained at different times from the same individual. 1035 44

The relationship between malignant potential and apoptosis in astrocytic tumors has not been clearly defined, and further classification of astrocytic tumors is necessary. To elucidate the relationship between the histopathological grade of astrocytic tumors and apoptosis, we studied 25 cases of astrocytic tumors, comprising 10 cases of glioblastoma (GB), 7 cases of anaplastic astrocytoma (AA), and 8 cases of astrocytoma (AC). We detected apoptosis using the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. We studied immunohistochemical expression of bcl-2 protein and p53 protein, which are apoptosis-related factors, and cell proliferative activity using Ki-67 antibody. No significant change was noted between apoptotic index and the histological grade of the tumors. In GB, apoptotic cell-rich foci were present at the pseudopalisading necrosis. No correlation between histopathological grades and expression of either p53 or bcl-2 was observed. In GB, however, poor distribution of bcl-2 was found in the areas of pseudopalisade formation. bcl-2 is one of the regulatory factors in the cell cycle and inhibits apoptosis. Expression of apoptosis had no correlation with histopathological grade. However, in GB, the distribution of apoptotic cells showed a correlation with bcl-2-poor foci. It was thought that apoptosis was one of the regulatory factors in the formation of pseudopalisading necrosis in GB.
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PMID:Expression of apoptosis and its related protein in astrocytic tumors. 1053 18

Glioblastomas develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). There is increasing evidence that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR and MDM2 amplification/overexpression, PTEN mutations, and p16 deletions, whereas secondary glioblastomas frequently contain p53 mutations. Loss of heterozygosity (LOH) on chromosome 10 (LOH#10) is the most frequent genetic alteration in glioblastomas; the involvement of tumor suppressor genes, other than PTEN, has been suggested. We carried out deletion mappings on chromosome 10, using PCR-based microsatellite analysis. LOH#10 was detected at similar frequencies in primary (8/17; 47%) and secondary glioblastomas (7/13; 54%). The majority (88%) of primary glioblastomas with LOH#10 showed LOH at all informative markers, suggesting loss of the entire chromosome 10. In contrast, secondary glioblastomas with LOH#10 showed partial or complete loss of chromosome 10q but no loss of 10p. These results are in accordance with the view that LOH on 10q is a major factor in the evolution of glioblastoma multiform as the common phenotypic end point of both genetic pathways, whereas LOH on 10p is largely restricted to the primary (de novo) glioblastoma.
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PMID:Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. 1065 4


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