Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homozygous chromosome 9p deletions in gliomas commonly include the CDKN2A and CDKN2B genes, which code for the structurally highly homologous cdk inhibitors/tumor suppressors p16 and p15, respectively. Alternative splicing of the CDKN2A gene results in the expression of p14(ARF). Interestingly, not only p16 and p15, but also the structurally unrelated p14(ARF) appear to function as negative cell cycle regulators. Concerted inactivation of p16, p15 and p14(ARF) could be demonstrated in seven of nine glioblastoma cell lines. Strong suppression of tumorigenicity after transfection with p16 and p15 alone or in combination was seen in cell lines containing neither endogenous p16 nor p15 but functional pRB. Significantly weaker growth suppression was observed in tumors either retaining expression of both p16 and p15 or p15 only. p14(ARF) proved to be a potent tumor suppressor in the presence of wild-type p53, while mutant p53 substantially reduced growth inhibition by p14(ARF). No differences between p16 and p15 effects could be observed, suggesting a largely overlapping function of p16 and p15. To facilitate further research into p16/p15 effects, three cell lines with conditional, tetracycline-controlled p16 expression were established. Reversible growth suppression mediated by p16 was observed in these models. Combined inactivation of CDKN2A and CDKN2B, i.e., loss of both p16 and p15 as well as p14(ARF), results in disruption of two major growth control pathways involving pRB and p53 in malignant gliomas. Therefore, homozygous co-deletions of CDKN2A and CDKN2B rather than mutations targeting individual transcripts are frequently selected for in these tumors.
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PMID:Functional evidence for a role of combined CDKN2A (p16-p14(ARF))/CDKN2B (p15) gene inactivation in malignant gliomas. 1054 65

In many human cancers, the INK4A locus is frequently mutated by homozygous deletions. By alternative splicing this locus encodes two non-related tumor suppressor genes, p16(INK4A) and p14(ARF) (p19(ARF) in mice), which regulate cell cycle and cell survival in the retinoblastoma protein (pRb) and p53 pathways, respectively. In mice, the role of p16(INK4A) as the critical tumor suppressor gene at the INK4A locus was challenged when it was found that p19(ARF) only knock-out mice developed tumors, including gliomas. We have analysed the genetic status of the INK4A locus in 105 primary gliomas using both microsatellite mapping (MSM) and quantitative real-time PCR (QRT-PCR). Comparison of the results of the two methods revealed agreement in 67% of the tumors examined. In discordant cases, fluorescence in situ hybridization (FISH) analysis was always found to support QRT-PCR classification. Direct assessment of p14(ARF) exon 1beta, p16(INK4A) exon 1alpha and exon 2 by QRT-PCR revealed 43 (41%) homozygous and eight (7%) hemizygous deletions at the INK4A locus. In 49 (47%) gliomas, both alleles were retained. In addition, QRT-PCR, but not MSM, detected hyperploidy in five (5%) tumors. Deletion of p14(ARF) was always associated with co-deletion of p16(INK4A) and increased in frequency upon progression from low to high grade gliomas. Shorter survival was associated with homozygous deletions of INK4A in the subgroup of glioblastoma patients older than 50 years of age (P=0.025, Anova test single factor, alpha=0.05).
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PMID:Quantitative real-time PCR does not show selective targeting of p14(ARF) but concomitant inactivation of both p16(INK4A) and p14(ARF) in 105 human primary gliomas. 1131 47

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
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PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98

Deletion of the INK4a-ARF locus is found in the majority of human malignant gliomas. However, the role of INK4a-ARF loss in gliomagenesis is unclear. Animal modeling has shown that mice with targeted deletions in the Ink4a-Arf gene do not develop spontaneous gliomas. We have previously reported that combined KRas and Akt signaling could induce glioblastoma (GBM) formation from neural progenitor cells but had no effect in differentiated astrocytes. In this investigation, we have studied the effects of Ink4a-Arf loss on the formation of GBM induced by KRas and Akt gene transfer into neural progenitor cells and astrocytes. We show here that Ink4a-Arf deficiency allows for GBM formation from astrocytes and that it enhances tumor incidence in neural progenitor cells. Furthermore, KRas alone can cooperate with deletion of the Ink4a-Arf locus in tumor formation from both neural progenitor cells and astrocytes. The resulting tumors were nestin positive and resembled a spectrum of glioma morphologies ranging in astrocytic character depending on cell-of-origin and presence of activated Akt. Our data strongly supports the view that one role of loss of Ink4a-Arf in gliomagenesis could be to sensitize astrocytes to transformation through dedifferentiation in response to the appropriate oncogenic stimuli.
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PMID:Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. 1235 67

Gliomas are tumors of the central nervous system with a wide spectrum of different tumor types. They range from pilocytic astrocytoma, with a generally good prognosis, to the extremely aggressive malignant glioblastoma. In addition to these 2 types of contrasting neoplasms, several other subtypes can be distinguished, each characterized by specific phenotypic, as well as genotypic features. Recently, the epigenotype, as evident from differentially methylated DNA loci, has been proposed to be useful as a further criterion to distinguish between tumor types. In our study, we screened 139 tissue samples, including 33 pilocytic astrocytomas, 46 astrocytomas of different grades, 7 oligoastrocytomas, 10 oligodendrogliomas, 10 glioblastoma multiforme samples and 33 control tissues, for methylation at CpG islands of 15 different gene loci. We used the semiquantitative high throughput method MethyLight to analyze a gene panel comprising ARF, CDKN2B, RB1, APC, CDH1, ESR1, GSTP1, TGFBR2, THBS1, TIMP3, PTGS2, CTNNB1, CALCA, MYOD1 and HIC1. Seven of these loci showed tumor specific methylation changes. We found tissue as well as grade specific methylation profiles. Interestingly, pilocytic astrocytomas showed no evidence of CpG island hypermethylation, but were significantly hypomethylated, relative to control tissues, at MYOD1. Our results show that glioma subtypes have characteristic methylation profiles and, with the exception of pilocytic astrocytomas, show both locus specific hyper- as well as hypomethylation.
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PMID:Distinct methylation profiles of glioma subtypes. 1279 56

Homozygous deletion of the INK4a-ARF locus is one of the most frequent mutations found in human glioblastoma. We have previously shown that combined Ink4a-Arf loss can increase tumor incidence in both glial progenitor cells and astrocytes during mouse gliomagenesis. Here we have investigated the separate contribution of loss of each of the tumor suppressor genes in glial progenitor cells and astrocytes in Akt + Kras-induced gliomagenesis. We show that Arf is the major tumor suppressor gene in both cell types. Arf loss generated glioblastomas from both nestin-expressing glial progenitor cells and glial fibrillary acidic protein-expressing astrocytes, with a significantly higher incidence in astrocytes. Ink4a loss, on the other hand, could only significantly contribute to gliomagenesis from glial progenitor cells and the induced tumors were of lower malignancy than those seen in Arf-deficient mice. Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment.
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PMID:Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis. 1578 13

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14(ARF)and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.
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PMID:Mutations in Rb1 pathway-related genes are associated with poor prognosis in anaplastic astrocytomas. 1597 Sep 25

To detect and identify the genetic alterations and methylation status of the HRK gene in human glioblastomas, we analyzed a cohort of astrocytic tumors for hypermethylation, loss of heterozygosity on 12q13.1, and gene expression. Our study examined a series of 36 diffuse low-grade astrocytomas, 32 anaplastic astrocytomas, 64 primary glioblastomas, and 28 secondary glioblastomas that had evolved from either 24 low-grade diffuse astrocytomas or 4 anaplastic astrocytomas. The region around the HRK transcription start site was methylated in 19% of diffuse astrocytomas, in 22% of anaplastic astrocytomas, in 27% of primary glioblastomas, and in 43% of secondary glioblastomas. HRK expression was significantly reduced in 61% of secondary glioblastomas as compared to other types of tumors, and aberrant methylation was closely associated with loss of expression. Reverse transcription-PCR analysis also demonstrated a clear agreement between reduced HRK protein levels and low or absent HRK transcripts. Lack of HRK immunoreactivity was significantly correlated with a low apoptotic index, whereas a strong association between methylation status and apoptosis was found only in secondary glioblastomas. Abnormal methylation of HRK was detected in astrocytic tumors concurrent with methylation of multiple genes, including p16(INK4a) and p14(ARF). Interestingly, these epigenetic changes in secondary glioblastoma were further associated with wild-type p53. Our findings suggest that HRK is inactivated mainly by aberrant DNA methylation in astrocytic tumors and that reduced HRK expression contributes to the loss of apoptotic control in high-grade tumors. Reduced expression of HRK may serve as one important molecular mechanism in progression to secondary glioblastoma.
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PMID:Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas. 1615 64

The aim of the present study was to elucidate genetic alterations that are critically involved in astrocytoma progression. We characterized 27 World Health Organization grade II fibrillary astrocytomas which later underwent recurrence or progression, paying specific attention to the CpG island methylation status of critical growth regulatory genes. p14(ARF) and O(6)-methylguanine-DNA methyltransferase (MGMT) hypermethylation represented frequent events (26% and 63%, respectively), which were mutually exclusive except in one case, with alternate or simultaneous methylation of these two genes occurring in 85% of our tumor series. Seventeen tumors (63%) contained TP53 mutations, which were closely related to the presence of MGMT methylation. Methylation of the p21(Waf1/Cip1), p27(Kip1) and p73 genes and homozygous deletion of the p16(INK4a), p15(INK4b) and p14(ARF) genes were not detected in any of the primary low-grade tumors. The presence of p14(ARF) methylation at first biopsy was associated with shorter patient survival, whereas the presence of MGMT methylation carried a better clinical outcome after salvage therapy. Examination of 20 cases whose histological data for recurrent tumors were available revealed that malignant progression occurred in all of the tumors with p14(ARF) methylation but less frequently (50%) in the lesions with MGMT methylation. On analysis of their respective recurrent tumors, five of six patients whose primary low-grade tumors carried p14(ARF) methylation exhibited homozygous co-deletions of the p14(ARF), p15(INK4b) and p16(INK4a) genes, which were restricted to glioblastoma as the most malignant end point. Our findings suggest that p14(ARF) hypermethylation and MGMT hypermethylation constitute distinct molecular pathways of astrocytoma progression, which could differ in biological behavior and clinical outcome.
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PMID:Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. 1749 32

Glioblastoma multiforme is the most common and most aggressive of the primary brain tumors. The mean survival of patients is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Cytogenetically, karyotypes of glioblastomas are very complex with trisomy 7 and monosomy 10 as the most frequent abnormalities. A genetic alteration that is significantly more frequent in primary than in secondary glioblastomas, the latter arising from preceding low-grade gliomas, is epidermal growth factor receptor gene (EGFR) amplification, whereas TP-53 mutations are significantly more frequent in low-grade gliomas and secondary glioblastomas derived there- from. We report the histological and genetic study of two glioblastomas, one case arising de novo and the other case arising 3 years after a previously diagnosed anaplastic astrocytoma, with concurrent EGFR amplification and TP-53 mutation. These anomalies were initially deemed as mutually exclusive. However, a small percentage of cases have been found with both anomalies although at a significantly lower level than could be expected. We have analyzed these two cases cytogenetically and by molecular studies in order to detect additional alterations associated with this phenotype. Cytogenetically, both cases showed in common the monosomy of chromosomes 10 and 17. At the molecular level, a rare mutation of TP-53 was found in the secondary glioblastoma and hypermethylation of the promoter region of p16(INK4a) and p14(ARF) genes were observed in the primary and secondary glioblastoma, respectively.
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PMID:Concurrent EGFR amplification and TP-53 mutation in glioblastomas. 1790 99


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