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

Gangliogliomas generally behave as benign indolent tumors. However, gangliogliomas undergoing malignant transformation have also been reported. The molecular basis for the malignant transformation of gangliogliomas remains unclear. We describe a case of ganglioglioma, which had transformed to glioblastoma after the gross total resection of the original tumor, in a 4-year-old girl. The present case is unusual in four aspects: (i) it arose from a low-grade ganglioglioma in the absence of previous radiation or chemotherapy, which is the fourth reported case; (ii) the original tumor showed a high proliferative index on flow cytometry but a low Ki-67 labeling index, implying that the application of flow cytometry might play a certain role in predicting biological and clinical behavior of low grade gangliogliomas; (iii) p53 mutation and deletion appeared in the secondary glioblastoma, which was not shown in the original well-differentiated ganglioglioma; and (iv) the transformed glioblastoma showed p16 inactivation detected by methylation and deletion, which are relatively uncommon genetic events in secondary glioblastomas. This is the first report of a genetic alteration in glioblastoma arising from a well differentiated ganglioglioma prior to radiation or chemotherapy. Based on the above findings, irrespective of radiotherapy or chemotherapy, rare recurrence of malignant evolution, especially tumors of high S-phase fraction on flow cytometry, warrants long-term follow-up, even in a well-differentiated ganglioglioma.
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PMID:Glioblastomatous transformation of ganglioglioma: case report with reference to molecular genetic and flow cytometric analysis. 1462 54

Amplification of the epidermal growth factor receptor (EGFR) or expression of its constitutively activated mutant, DeltaEGFR(2-7), in association with the inactivation of the INK4a/Arf gene locus is a frequent alteration in human glioblastoma. The notion of a cooperative effect between these two alterations has been demonstrated in respective mouse brain tumor models including our own. Here, we investigated underlying molecular mechanisms in early passage cortical astrocytes deficient for p16(INK4a)/p19(Arf) or p53, respectively, with or without ectopic expression of DeltaEGFR(2-7). Targeting these cells with the specific EGFR inhibitor tyrphostin AG1478 revealed that phosphorylation of ERK was only abrogated in the presence of an intact INK4a/Arf gene locus. The sensitivity to inhibit ERK phosphorylation was independent of ectopic expression of DeltaEGFR(2-7) and independent of the TP53 status. This resistance to downregulate the MAPK pathway in the absence of INK4a/Arf was confirmed in cell lines derived from our mouse glioma models with the respective initial genetic alterations. Thus, deletion of INK4a/Arf appears to keep ERK in its active, phosphorylated state insensitive to an upstream inhibitor specifically targeting EGFR/DeltaEGFR(2-7). This resistance may contribute to the cooperative tumorigenic effect selected for in human glioblastoma that may be of crucial clinical relevance for treatments specifically targeting EGFR/DeltaEGFR(2-7) in glioblastoma patients.
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PMID:INK4a/Arf is required for suppression of EGFR/DeltaEGFR(2-7)-dependent ERK activation in mouse astrocytes and glioma. 1527 38

We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months (<50 years) to 1.6 months (>80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16(INK4a) deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.
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PMID:Genetic pathways to glioblastoma: a population-based study. 1546 78

Five malignant glioma cell lines (YMG1, 2, 3, 4, and 5) were established from surgical specimens obtained from patients with glioblastoma or anaplastic astrocytoma, and these lines were partially characterized. Three glioma cell lines (YMG1, 3, and 5) were weakly positive for GFAP by Western blot analysis and two cell lines were negative. S-100 protein was positive in all glioma cell lines. The expression of p53, p16, p15, cyclin-dependent kinase 4 (CDK4), and EGF receptor (EGFR) proteins was examined by Western blotting. YMG1 and 2 cell lines showed accumulation of p53 protein and loss of p16 and p15 expression. YMG3 and 4 showed accumulation of p53 protein and expression of p16 and p15 proteins. YMG5 revealed weak expression of p53 protein, suggesting wild-type p53, and loss of p16 and p15 expression. All cell lines expressed various levels of CDK4 protein. YMG1, 2, and 3 showed higher EGFR protein expression and YMG4 and 5 showed lower EGFR expression compared to U251 glioblastoma cells, which express high levels of EGFR. Fluorescence in situ hybridization analysis for EGFR gene expression did not show any amplification in the glioma cell lines. Immunohistochemical studies revealed that the patterns of p53 and EGFR expressions in the original tumor tissues were mostly correlated with those in the malignant glioma cell lines. These results suggest that the characteristics of p53 and EGFR expression in the malignant glioma cell lines were passed over from the original tumor tissues. These newly established malignant glioma cell lines can be used for further analysis of the mechanisms of tumor growth and progression.
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PMID:Establishment and partial characterization of five malignant glioma cell lines. 1587 6

Glioblastomas, the most frequent and malignant glial tumors, are known to be phenotypically heterogeneous. A low fraction of glioblastomas is associated with specific chromosomal losses at 1p and 19q, which are commonly found in oligodendrogliomas and are generally considered to be a primary event in the development of these tumors. Subsequent progression of oligodendroglial tumors appears to be triggered by additional molecular features underlying the transition to anaplastic oligodendroglioma and glioblastoma multiforme (GBM) such as deletions of 9p and 10q, and alterations of CDKN2A (p16), which is located at 9p21. These findings strengthen the view that GBM on rare occasions may develop from oligodendroglial differentiated cells. In the present study, we evaluated the newly established MI-4 glioblastoma cell line, which displays 1p and 19q specific alterations targeting preferential regions of allelic loss in glial neoplasms, by array-CGH and fluorescence in situ hybridization (FISH) analyses that were combined to obtain a high resolution map of targeted chromosome rearrangements and copy number changes throughout the genome. Genome-wide and chromosome 19 full coverage array-CGH analysis of the MI-4 cell line revealed that in this particular cell line, 1p-specific loss, including the CDKN2 (p18) gene, is not accompanied by loss of the previously described 19q13.3 tumor suppressor candidate region. Interestingly, the array-CGH (CGHa) profile showed an increase in copy number along most of 19q including the AKT2 oncogene and the KLKs gene family, which have previously been shown to be amplified in pancreatic carcinomas and upregulated in several tumors, respectively. The concomitant 1p partial loss and chromosome 19 alterations, with the +7 and -10-specific GBM markers associated with homozygous deletion of 9p21.3 including CDKN2A (p16), are distinct features of the glioblastoma MI-4 cell line, illustrating its origin from an olidodendroglial tumor. Based on these results, we conclude that the MI-4 glioblastoma cell line might function as a model system for investigations into the behavior of a defined oligodendroglioma subtype.
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PMID:Identification of oligodendroglioma specific chromosomal copy number changes in the glioblastoma MI-4 cell line by array-CGH and FISH analyses. 1610 84

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

Identification of genetic copy number changes in glial tumors is of importance in the context of improved/refined diagnostic, prognostic procedures and therapeutic decision-making. In order to detect recurrent genomic copy number changes that might play a role in glioma pathogenesis and/or progression, we characterized 25 primary glioma cell lines including 15 non glioblastoma (non GBM) (I-III WHO grade) and 10 GBM (IV WHO grade), by array comparative genomic hybridization, using a DNA microarray comprising approx. 3500 BACs covering the entire genome with a 1 Mb resolution and additional 800 BACs covering chromosome 19 at tiling path resolution. Combined evaluation by single clone and whole chromosome analysis plus 'moving average (MA) approach' enabled us to confirm most of the genetic abnormalities previously identified to be associated with glioma progression, including +1q32, +7, -10, -22q, PTEN and p16 loss, and to disclose new small genomic regions, some correlating with grade malignancy. Grade I-III gliomas exclusively showed losses at 3p26 (53%), 4q13-21 (33%) and 7p15-p21 (26%), whereas only GBMs exhibited 4p16.1 losses (40%). Other recurrent imbalances, such as losses at 4p15, 5q22-q23, 6p23-25, 12p13 and gains at 11p11-q13, were shared by different glioma grades. Three intervals with peak of loss could be further refined for chromosome 10 by our MA approach. Data analysis of full-coverage chromosome 19 highlighted two main regions of copy number gain, never described before in gliomas, at 19p13.11 and 19q13.13-13.2. The well-known 19q13.3 loss of heterozygosity area in gliomas was not frequently affected in our cell lines. Genomic hotspot detection facilitated the identification of small intervals resulting in positional candidate genes such as PRDM2 (1p36.21), LRP1B (2q22.3), ADARB2 (10p15.3), BCCIP (10q26.2) and ING1 (13q34) for losses and ECT2 (3q26.3), MDK, DDB2, IG20 (11p11.2) for gains. These data increase our current knowledge about cryptic genetic changes in gliomas and may facilitate the further identification of novel genetic elements, which may provide us with molecular tools for the improved diagnostics and therapeutic decision-making in these tumors.
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PMID:Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines. 1624 47

Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.
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PMID:Genetic alterations in primary glioblastomas in Japan. 1641 Jul 44

Glioblastomas are histologically and genetically heterogeneous. We have investigated to what extent histologic features reflect the genetic profile and whether they are predictive of clinical outcome. Key histologic characteristics, including major cell types (small cell, nonsmall cell), other components such as oligodendroglial components, gemistocytes, multinucleated giant cells, as well as necrosis and microvascular proliferation, of 420 cases of glioblastoma within a population-based study (1) were reassessed and correlated with patients' clinical outcome and key genetic alterations. EGFR amplification and p16 homozygous deletion were significantly more frequent in small cell glioblastomas than in nonsmall cell glioblastomas (EGFR, 46% vs 26%, p = 0.0002; p16 39% vs 25%, p = 0.0167). Multivariate analyses with adjustment for age and gender showed that small cell glioblastomas had frequent EGFR amplification and p16 deletion but infrequent PTEN mutations. An oligodendroglial component was detected in 20% of glioblastomas; these patients were significantly younger (54.4 +/- 13.6 vs 59.2 +/- 13.8 years; p = 0.0049) and survived longer (10.3 +/- 8.3 vs 8.2 +/- 8.4 months; p = 0.0647). However, multivariate analyses with adjustment for age and gender did not show the presence of an oligodendroglial component to be predictive of longer survival. After adjustment for age and gender, LOH 1p was associated with longer survival (hazard ratio, 0.7; 95% confidence interval [CI], 0.5-1.0), whereas LOH 10q was associated with shorter survival (hazard ratio, 1.4; 95% CI, 1.0-1.8) of patients with glioblastoma. Glioblastomas containing >or=5% multinucleated giant cells showed more frequent TP53 mutation and infrequent EGFR amplification than those containing <5% multinucleated giant cells (TP53, 45% vs 24%, p = 0.0001; EGFR, 24% vs 42%, p = 0.0005). Vascular proliferation was observed in all glioblastomas, whereas large ischemic and/or pseudopalisading necrosis was observed in 366 of 420 (87%) cases. Glioblastomas with necrosis were associated with older age (59.2 +/- 13.3 vs 51.6 +/- 15.3 years; p = 0.0001) and shorter survival (7.9 +/- 6.8 vs 12.9 +/- 14.2 months; p = 0.0017). Multivariate analyses with adjustment for age and gender confirmed this observation (hazard ratio, 1.5; 95% CI, 1.1-2.0). Multivariate analysis with adjustment for age and gender showed that necrosis was significantly associated with wild-type TP53 and absence of an oligodendroglial component. These results suggest that some histologic features in glioblastomas are associated with specific genetic alterations and with clinical outcome.
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PMID:Correlation among pathology, genotype, and patient outcomes in glioblastoma. 1695 78

Several studies have suggested that hypermethylation and hypomethylation of CpG islands within the promoters and 5' exons of tumor-related genes are closely associated with carcinogenesis. However, large-scale analysis of candidate genes has been hampered by the lack of a high throughput approach for analyzing methylation patterns. Using methylation-specific oligonucleotide (MSO) chips, we evaluated the methylation patterns of eight samples of fresh frozen glioblastoma tissue. The MSO chip used contained DNA probes with the CpG sites of p16 (p16INK4A, CDKN2A), MGMT (O6-Methylguanine-DNA-methyltransferase), APC (adenomatous polyposis coil), RASSF1A (human RAS effect homolog), which are usually hypermethylated in cancer cells and MAGE (melanoma antigen), which is usually hypomethylated in cancer cells. We selected CpG sites for analysis; 28 CpG sites (263 bp) for p16, 26 CpG sites (249 bp) for MGMT, 16 CpG sites (195 bp) for APC, 22 CpG sites (262 bp) for RASSF1A and 18 CpG sites (235 bp) for MAGE. We then constructed primer sets not including CpG sites. Bisulfite modification of genomic DNA, methylation specific PCR, hybridization and image scan with data analysis and sequencing of the bisulfite modified DNA were carried out. Of the eight glioblastomas, hypermethylation of the 5'-CpG sites of the MGMT were found in two, RASSF1A were found in five, and p16 and APC genes were not found in any cases and hypomethylation of that of the MAGE was found in eight cases. These results obtained from the oligo DNA chip study were correlated well with the sequencing data of bisulfite modified genomic DNA except in regard to the RASSF1A and MAGE genes. The devised MSO DNA chip is a useful tool for studies on methylation.
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PMID:Oligonucleotide DNA chips are useful adjuncts in epigenetic studies of glioblastomas. 1708 Jul 17


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