Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genes involved in the genesis and progression of adult astrocytic tumors have been an area of considerable investigation. The tumor suppressor gene, p53, has been implicated, as has the epidermal growth factor receptor gene. Additional currently unidentified genes lie on chromosomes 10 and 19. Interestingly, work on pediatric astrocytomas suggests that the genes involved are different. p53 is rarely mutated in pediatric tumors, the epidermal growth factor receptor gene is rarely amplified or mutated, and chromosome 10 deletions are rare. The only pediatric tumor that seems to mimic the findings in adult tumors is brainstem glioma, perhaps explaining the uniformly grim prognosis in this type of tumor. In the pilocytic astrocytoma of childhood, mutations in the neurofibromatosis type I gene have been implicated in tumor development. In this review, the oncogenesis of pediatric gliomas is discussed and compared and contrasted to what is known about tumors.
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PMID:Molecular biology of pediatric gliomas. 883 57

Pleomorphic xanthoastrocytoma (PXA) is a low-grade glioma that may recur as a malignant diffuse astrocytoma such as glioblastoma (GBM). While the molecular genetic basis of diffuse astrocytomas has been studied extensively, PXAs have not been analyzed in detail. We, therefore analyzed DNA from archival primary and recurrent PXAs from eight patients (three grade II PXAs without recurrence, one grade II PXA with recurrence as grade II PXA, two grade II PXAs with progression to GBM, and two grade III anaplastic PXAs with recurrence as grade III anaplastic PXA or GBM) for genetic changes associated with diffuse astrocytomas. Single-strand conformation polymorphism analysis of p53 exons 5-8 revealed migration shifts in two cases, one primary PXA without recurrence and one recurrent grade II PXA in which the primary tumor did not show a shift. DNA sequencing showed two missense mutations in codons 220 (exon 6) and 292 (exon 8), respectively, mutations which have not been previously noted in astrocytomas. Differential polymerase chain reaction analysis demonstrated epidermal growth factor receptor gene amplification in only one tumor, a GBM without allelic loss of chromosome 10 that was the second GBM recurrence of an initial grade II PXA. Loss of heterozygosity studies on tumors from five patients, using three microsatellite polymorphisms on chromosome 10q and three on chromosome 19q, did not disclose allelic loss in any recurrent tumor. These findings suggest that the genetic events that underlie PXA formation and progression may differ significantly from those involved in diffuse astrocytoma tumorigenesis.
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PMID:Molecular genetic alterations in pleomorphic xanthoastrocytoma. 883 42

A total of 10 glioma cell lines were examined for alterations of the p16, p15, p53 and p21 genes, which are tumor suppressor genes or candidates with direct or indirect CDK-inhibitory functions. Genetic alterations (deletions or mutations) were frequently seen in the p16, p15 and p53 genes in these cell lines, but not in the p21 gene. When the states of the p16, p15 and p53 genes were compared among cell lines, all the cell lines showed abnormalities in at least 1 gene, often in 2 or 3 genes coincidentally, suggesting that dysfunction of these genes is closely related to glioma cell growth. Although alteration of all 3 genes was most frequent, there were cell lines having either p16/p15 or p53 or pl6 and p53 gene alterations, suggesting that the time order of these genetic alterations was variable depending on the cell line. Among cell lines examined, one with homozygous p53 gene deletion seemed of particular practical value, since such a cell line might be useful in various studies, including investigation of the functions of various mutant p53 genes in the absence of heteromeric protein formation. On examination of the primary tumor tissues, the same alterations of the p16/p15 and p53 genes as detected in the cell lines were demonstrated in all 6 cases examined: p16/p15 gene deletion in 1, p16 gene mutation in 1 and p53 gene mutations in 5 cases. This suggested that the p16/p15 and the p53 gene alterations and their combinations in at least some glioma cell lines reflected those in the primary glioma tissues.
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PMID:A comparative study of glioma cell lines for p16, p15, p53 and p21 gene alterations. 887 51

Ependymomas are glial tumors of the brain and spinal cord occurring both sporadically and in a familial syndrome, neurofibromatosis type 2 (NF2). Previous analyses performed on specimens obtained predominantly from adult patients have shown loss of DNA sequences from chromosome arm 22q, which is the location of the NF2 gene. Previously, we documented the consistent loss of chromosome arm 17p DNA in medulloblastoma and astrocytoma, which are the most common brain tumors in children. Although mutation of the TP53 gene located on 17p is the most frequent genetic mutation in all adult tumor types, such mutations are rare in most childhood brain tumors investigated to date. We studied a series of pediatric ependymoma specimens (16 intracranial and 2 spinal) for loss of 17p and 22q DNA sequences and for mutation of the TP53 and NF2 genes. None of the children had the clinical stigmata of NF2. We detected loss of 17p DNA sequences in 9 of the 18 specimens (50%); in 7 of 9 of these specimens (78%), the 144-D6 marker was deleted. In contrast, only 2 of these same 18 specimens (11%) showed loss of 22q DNA. One TP53 gene mutation was detected in a child from a cancer kindred. No mutations were detected in the NF2 gene. Our results suggest that loss of chromosome arm 17p DNA sequences is common in sporadic pediatric ependymomas and that, in contrast to ependymomas in adults, deletion of chromosome arm 22q sequences is rare. Furthermore, TP53 and NF2 gene mutations do not play an important role in the etiology of sporadic pediatric ependymomas.
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PMID:Molecular genetic analysis of chromosome arm 17p and chromosome arm 22q DNA sequences in sporadic pediatric ependymomas. 888 5

Seven human glioma cell lines were examined for mutations of the p53 gene and their mRNA and protein expressions. Five cell lines revealed a missense mutation at, codons 237, 245, or 273. Their p53 mRNA expression was variably distinct and not always comparable to p53 protein expression, suggesting difference in the transcriptional and posttranscriptional regulation. One cell line had a splicing mutation in intron 9 and abnormal splicing was actually demonstrated by RT-PCR analysis. The remaining 1 cell line showed no PCR-amplification of the p53 gene sequence. In an examination of the original tumor tissues, the same mutations were demonstrated in the 5 tumors examined, strongly suggesting that the mutations in the glioma cell lines were derived from their original tumor tissues.
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PMID:Analysis of p53 gene mutations in human glioma cell lines. 891 20

It is proposed that genomic integrity is preserved after DNA damage in a variety of ways. X irradiation induces a p53-dependent G1-phase cell cycle checkpoint which putatively allows time for repair of DNA damage. The p53 protein is also involved in the initiation of apoptosis after radiation-induced DNA damage, presumably leading to the elimination of lethally damaged cells from the irradiated population. To test the hypothesis that repair occurs in the additional time provided by the activation of the G1-phase checkpoint, we investigated whether the presence of a G1-phase arrest modified the frequency and type of chromosomal rearrangements at the first mitosis after irradiation. Isogenic cell lines derived from the same human glioma cell line, but differing in p53 status, were used. Purified G1-phase cells, isolated by centrifugal elutriation and X-irradiated, were studied. The wild-type p53 cell line demonstrated a dose-dependent arrest during G1 phase, as determined by flow cytometry. These cells remained in G1-phase as long as 48 h after irradiation. Cells expressing a dominant-negative p53 mutation accumulated to a much lesser extent in G1 phase after irradiation. Cells lacking the G1-phase checkpoint showed increased survival at all radiation doses. There were no significant differences in the type or frequency of total chromosomal aberrations in mitotic cells from either cell line after 1,2,4 or 6 Gy X rays, as measured by conventional cytogenetic analysis. There was an increase, however, in the number of reciprocal translocations in mitotic cells with mutant p53 (lacking a G1-phase checkpoint), as measured by fluorescence in situ hybridization with a chromosome 4-specific DNA library, but only after 6 Gy. The results suggest that the presence of a well-defined p53-dependent G1-phase arrest does not reduce chromosomal aberrations caused by low doses of ionizing radiation markedly, but may reduce the overall degree of survival by triggering other G1-phase events.
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PMID:Cytogenetic damage and the radiation-induced G1-phase checkpoint. 892 96

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a seco-steroid hormone with potential antitumoral activities, has been recently reported to exert cytotoxic effects on C6 glioma cells. However, the molecular mechanisms which trigger this cell death remain unknown. We show here that this 1,25(OH)2D3-induced cell death is dependent upon protein synthesis and is accompanied by the expression of c-myc, p53, and gadd45 genes. Two other genes, coding for interleukin-6 and vaso-endothelial growth factor, are also upregulated after addition of 1,25(OH)2D3. This programmed cell death can be suppressed when cells are treated with forskolin, a drug which increases intracellular cAMP concentration, or with genistein, an inhibitor of tyrosine protein kinases. However, in spite of the demonstration of fragmented DNA in 1,25(OH)2D3-treated cells, the C6.9 cells used in this study do not show the classical morphological features of apoptosis. These results provide the first evidence for the existence of a programmed cell death triggered by 1,25(OH)2D3 in glioma cells and may provide a basis for the development of new therapeutic strategies. In addition, these data also suggest that the treatment of C6.9 cells with 1,25(OH)2D3 may be a useful model to study the molecular mechanisms involved in the programmed cell death of a cell of glial origin.
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PMID:1,25-Dihydroxyvitamin D3 induces programmed cell death in a rat glioma cell line. 895 66

The prognosis for children with high-grade gliomas remains somewhat unpredictable. Although prolonged disease control is sometimes achieved after surgery, radiotherapy, and chemotherapy, most patients exhibit rapid disease progression. Because p53-dependent apoptosis mechanisms are involved in the cytotoxic effects of irradiation and chemotherapy, we questioned whether p53 status might be associated with outcome in childhood malignant gliomas. Therefore, we examined p53 status, both immunohistochemically and by direct sequencing of exons 5-8, in a series of 29 archival pediatric malignant non-brainstem gliomas treated consecutively at our institution between 1975 and 1992. Eighteen tumors had dense p53 staining in the majority of cells, although only 11 had mutations of the p53 gene (TP53). On univariate analysis, there was a significant association between p53 overexpression and a shorter progression-free survival (PFS) and overall survival (OS; P = 0.019 and 0.013, respectively; rank sum test). In addition, there was a significant association between TP53 mutations and a poorer PFS (P = 0.04), and a strong trend toward a shorter OS among patients with TP53 mutations (P = 0.06). Median PFS and OS for patients with TP53-mutated tumors were 6 months and 16 months, respectively, and for those with p53 overexpression 5.5 months and 14 months, respectively, versus 16 months and 25 months, respectively, for those without TP53 mutations and 25 months and >4 years, respectively, for those without p53 overexpression. The percentage of patients in this series with TP53 mutations (37.9%) was substantially higher than in previous studies of childhood gliomas and comparable to the frequency of mutations noted in adult gliomas. However, both TP53 mutation and p53 overexpression were significantly less frequent in tumors from children younger than 4 than from older children (P = 0.02 and 0.01, respectively). These results indicate that p53 mutation and expression status may be associated with prognosis in childhood malignant gliomas, and thus may provide a basis for stratifying patients biologically in future malignant glioma studies.
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PMID:The relationship between TP53 mutations and overexpression of p53 and prognosis in malignant gliomas of childhood. 900 May 73

Malignant glioma cells are susceptible to CD95(Fas/APO-)-mediated apoptosis triggered by agonistic antibody. Here we examined the proapoptotic effects of the natural CD95 ligand, a cytotoxic cytokine homologous to tumor necrosis factor, on malignant glioma cell lines LN-229, LN-308 and T98G. We assessed whether glioma cell killing is synergistically enhanced by cotreatment with CD95 ligand and chemotherapeutic agents, including doxorubicin, carmustine, vincristine, etoposide, teniposide, 5-fluorouracil and cytarabine. Synergy was examined at low concentrations of cytotoxic drugs and CD95 ligand with a defined effect level (IC15). Short-term-cytotoxicity assays showed prominent killing of the glioma cells by CD95 ligand but not by the drugs at relevant concentrations. CD95 ligand induced apoptosis in the acute toxicity paradigm was augmented by doxorubicin and vincristine. Growth-inhibition assays revealed prominent synergy between CD95 ligand and all drugs examined. The best synergy was obtained with CD95 ligand and doxorubicin, vincristine or teniposide. The strong synergistic antiproliferative effects were observed at much lower concentrations of CD95 ligand and cytotoxic drugs than the moderate synergistic acute cytotoxic effects. All cell lines examined express the Bcl-2 protein. LN-229 has partial wild-type p53 activity. T98G has mutant p53, LN-308 has a deleted p53 gene and lacks p53 protein expression. Thus, synergistic effects of CD95 ligand and cytotoxic drugs were observed in cell lines exhibiting two features thought to play a role in the chemoresistance of human malignant glioma cells: loss of wild-type p53 activity and acquisition of bcl-2 expression. Ectopic expression of murine bcl-2 conferred partial protection from CD95 ligand and drugs when administered alone but did not interfere with the mechanisms underlying the synergistic effects of CD95 ligand and chemotherapeutic drugs.
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PMID:Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. 911 85

Wild-type human p53 gene was transfected into the human glioma cell line T-98G. Transfectants were then isolated and characterized for growth potential and differentiation phenotype. Growth suppression, overexpression of GFAP, and accumulation in G1 phase were more commonly observed in transfectants than in T-98G cells. p21WAF1/CIP1 was overexpressed in transfectants, and the binding of PCNA and CDK 2 to p21WAF1/CIP1 were increased in transfectants. These results suggested the roles of p21WAF1/CIP1, PCNA, and CDK2 in regulation of differentiation in glioma cells and the gene transfer of wild-type p53 may be effective for the control of glial differentiation in glioma cells.
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PMID:Induction of differentiation by wild-type p53 gene in a human glioma cell line. 912 May 41


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