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  • Glioblastoma
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  • 1
    Language: English
    In: Cancer, 15 August 2005, Vol.104(4), pp.825-32
    Description: In patients with glioblastoma, age 〈 50 years was identified as a consistent prognostic variable. In addition, the prognosis for these patients may be determined by a complex interaction between age and genetic alterations. The objective of the current study was the molecular analysis of glioblastomas from adult patients age 〈 50 years ("young adults"). The authors analyzed a set of 189 glioblastoma specimens. Fluorescence in situ hybridization was performed with a set of 10 chromosome probes (1p36, 1q25, centomere probe 7 [CEP7], 7p12/epidermal growth factor receptor gene (EGFR), CEP9, 9p21/p16, CEP10, 10q23/phosphatase and tesnin homolog gene (PTEN), 19p13, and 19q13). Patient age or = 40 years frequently showed EGFR amplification, loss of 9p, loss of 10q, and gain of chromosome 19. The patients with - 19q were age 40 years were examined separately. Consequently, EGFR amplification, - 9p, and + 9 were significant for both age groups, whereas gain of chromosome 7 and loss of 10q showed clinical importance only among patients age 〉 40 years. Adult patients age 〈 50 years with glioblastoma had molecularly distinct disease, and the age-dependent heterogeneity seen on the chromosomal level also applied at the clinical level.
    Keywords: Brain Neoplasms -- Genetics ; Glioblastoma -- Genetics
    ISSN: 0008-543X
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  • 2
    In: Oncogene, 2011, Vol.31(27), p.3235
    Description: The concept of cancer stem-like cells (CSCs) has gained considerable attention in various solid tumors including glioblastoma, the most common primary brain tumor. This sub-population of tumor cells has been intensively investigated and their role in therapy resistance as well as tumor recurrence has been demonstrated. In that respect, development of therapeutic strategies that target CSCs (and possibly also the tumor bulk) appears a promising approach in patients suffering from primary brain tumors. In the present study, we utilized RNA interference (RNAi) to screen the complete human kinome and phosphatome (682 and 180 targets, respectively) in order to identify genes and pathways relevant for the survival of brain CSCs and thereby potential therapeutical targets for glioblastoma. We report of 46 putative candidates including known survival-related kinases and phosphatases. Interestingly, a number of genes identified are involved in metabolism, especially glycolysis, such as PDK1 and PKM2 and, most prominently PFKFB4. In vitro studies confirmed an essential role of PFKFB4 in the maintenance of brain CSCs. Furthermore, high PFKFB4 expression was associated with shorter survival of primary glioblastoma patients. Our findings support the importance of the glycolytic pathway in the maintenance of malignant glioma cells and brain CSCs and imply tumor metabolism as a promising therapeutic target in glioblastoma. Keywords: loss-of-function screen; apoptosis; glioblastoma; cancer stem-like cells; glycolysis
    Keywords: Cancer Cells – Physiological Aspects ; Cancer Cells – Genetic Aspects ; Cancer Cells – Research ; Gliomas – Genetic Aspects ; Gliomas – Research ; RNA Interference – Research ; RNA Interference – Physiological Aspects;
    ISSN: 0950-9232
    E-ISSN: 14765594
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  • 3
    In: Nature, 2012, Vol.482(7384), p.226
    Description: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases (1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX([alpha]-thalassaemia/mental retardation syndrome X-linked) (5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres (6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.
    Keywords: Gene Mutation -- Research ; Dna -- Research ; Dna -- Physiological Aspects ; Glioblastomas -- Genetic Aspects ; Glioblastomas -- Research ; Tumor Proteins -- Physiological Aspects ; Tumor Proteins -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: Journal of Clinical Neuroscience, November 2014, Vol.21(11), pp.1945-1950
    Description: We report a 64-year-old woman who underwent craniotomy and gross total resection of a left frontal lobe tumor initially diagnosed as glioblastoma. Multiple wound revisions were necessary due to repeated wound healing disorders under concomitant radio-chemotherapy. After 9 months there was local cranial tumor recurrence, requiring re-operation. Thereafter, temozolomide monotherapy was implemented. Histologically, a shift from glial to mesenchymal differentiation was observed in the recurrent tumor, resulting in the diagnosis of gliosarcoma. A further 9 months later a thoracic spinal tumor occurred requiring emergency tumor resection. Analysis showed a mesenchymal tumor without definite glial component. Being resistant to local radiation therapy, symptomatic local spinal tumor progression was observed within 1 month requiring re-resection. There was no response to chemotherapy with bevacizumab and irinotecan. Considering the pronounced sarcoma-like differentiation, a sarcoma chemotherapy regime with doxorubicin was initiated. This was also to no avail; the disease progressed and recurred at both the spinal and cerebral locations, respectively. This ambiguous tumor characteristic and therapy resistance encouraged us to retrospectively perform molecular and array-based comparative genomic hybridization (aCGH) analysis on the extirpated cerebral and spinal tumors. Tumors from both locations showed a consistent cytogenetic signature of gain of chromosome 7, and losses of chromosomes 10 and 13. This novel report of aCGH analysis of spinal gliosarcoma metastasis and the correlation to the clinical disease course shows that genotypic profiling may serve as a supplementary diagnostic tool in improving our knowledge of the biologic behavior of rare tumor variants.
    Keywords: Comparative Genomic Hybridization ; Glioblastoma ; Gliosarcoma ; Spinal Metastasis ; Medicine
    ISSN: 0967-5868
    E-ISSN: 1532-2653
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  • 5
    Language: English
    In: Cancer, 15 August 2005, Vol.104(4), pp.825-832
    Description: BACKGROUND: In patients with glioblastoma, age 〈 50 years was identified as a consistent prognostic variable. In addition, the prognosis for these patients may be determined by a complex interaction between age and genetic alterations. The objective of the current study was the molecular analysis of glioblastomas from adult patients age 〈 50 years ("young adults").METHODS: The authors analyzed a set of 189 glioblastoma specimens. Fluorescence in situ hybridization was performed with a set of 10 chromosome probes (1p36, 1q25, centomere probe 7 [CEP7], 7p12/epidermal growth factor receptor gene (EGFR), CEP9, 9p21/p16, CEP10, 10q23/phosphatase and tesnin homolog gene (PTEN), 19p13, and 19q13).RESULTS: Patient age 〈 40 years was associated strongly with a favorable prognosis. Patients age 〉 or = 40 years frequently showed EGFR amplification, loss of 9p, loss of 10q, and gain of chromosome 19. The patients with - 19q were age 〈 40 years. The survival was shorter for patients with EGFR amplification, gain of chromosome 7, loss of 9p, loss of 10q, and gain of chromosome 19. In contrast, the patients who had tumors with gain of chromosome 9 or loss of 19q had more favorable outcomes. In a multivariate analysis, gain of chromosome 9 (P = 0.026) and loss of 10q23 (P = 0.007) reached the level of independent prognostic value. In addition, the prognostic value of molecular alterations in patients age 〈 40 years and patients age 〉 40 years were examined separately. Consequently, EGFR amplification, - 9p, and + 9 were significant for both age groups, whereas gain of chromosome 7 and loss of 10q showed clinical importance only among patients age 〉 40 years.CONCLUSIONS: Adult patients age 〈 50 years with glioblastoma had molecularly distinct disease, and the age-dependent heterogeneity seen on the chromosomal level also applied at the clinical level.
    Keywords: Glioblastoma ; Young Adults ; Molecular Analysis ; Prognosis
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 6
    Language: English
    In: Acta neuropathologica, September 2017, Vol.134(3), pp.507-516
    Description: Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.
    Keywords: Brain Tumor ; Egfr ; Glioblastoma ; Mycn ; Methylation ; Pdgfra ; Pediatric ; Prognostic ; Rtk ; Subgroup ; Survival ; Mutation ; Brain Neoplasms -- Genetics ; Glioblastoma -- Genetics ; Histones -- Genetics ; Isocitrate Dehydrogenase -- Genetics
    ISSN: 00016322
    E-ISSN: 1432-0533
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  • 7
    Language: English
    In: Acta Neuropathologica, 2018, Vol.136(2), pp.273-291
    Description: Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1 , followed by BRAF and FGFR1 ) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX , affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
    Keywords: Anaplastic pilocytic astrocytoma ; Pilocytic astrocytoma with anaplasia ; Methylation profile based classification ; Panel sequencing ; ATRX ; BRAF ; NF1 ; FGFR1 ; MGMT ; CDKN2A/B ; Molecular characterization ; DNA copy number alterations
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 8
    Language: English
    In: Cell, 23 May 2013, Vol.153(5), pp.1064-1079
    Description: Metabolic adaptation is essential for cell survival during nutrient deprivation. We report that eukaryotic elongation factor 2 kinase (eEF2K), which is activated by AMP-kinase (AMPK), confers cell survival under acute nutrient depletion by blocking translation elongation. Tumor cells exploit this pathway to adapt to nutrient deprivation by reactivating the AMPK-eEF2K axis. Adaptation of transformed cells to nutrient withdrawal is severely compromised in cells lacking eEF2K. Moreover, eEF2K knockdown restored sensitivity to acute nutrient deprivation in highly resistant human tumor cell lines. In vivo, overexpression of eEF2K rendered murine tumors remarkably resistant to caloric restriction. Expression of strongly correlated with overall survival in human medulloblastoma and glioblastoma multiforme. Finally, strains deficient in , the ortholog, were severely compromised in their response to nutrient depletion. Our data highlight a conserved role for eEF2K in protecting cells from nutrient deprivation and in conferring tumor cell adaptation to metabolic stress. Tumor cells adapt to the stress of nutrient deprivation by increasing the activity of translation elongation factor 2 kinase (eEF2K), which protects cells from apoptosis by inhibiting the elongation step of mRNA translation.
    Keywords: Biology
    ISSN: 0092-8674
    E-ISSN: 1097-4172
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  • 9
    Language: English
    In: Acta Neuropathologica, 2011, Vol.121(3), pp.397-405
    Description: Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 ( BRAF ) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF V600E mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF V600E mutation was strongly associated with extra-cerebellar location ( p  = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF V600E mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF V600E mutant brain tumor patients will benefit from BRAF V600E -directed targeted therapies.
    Keywords: BRAF ; V600E mutation ; Brain tumor ; Pleomorphic xanthoastrocytoma ; Ganglioglioma
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 10
    In: Journal of Neuropathology & Experimental Neurology, 2016, Vol.75(5), pp.408-414
    Description: Glioblastomas (GBMs) are malignant brain tumors that can be divided into different molecular subtypes based on genetics, global gene expression, and methylation patterns. Among these subgroups, “IDH” GBMs carry mutations within IDH1 or IDH2. The “K27” and “G34” subgroups are characterized by distinct mutations within Histone 3 (H3). These subtypes can be identified by sequencing methods and are particularly found in younger patients. To determine whether the molecular subtypes correlate with distinct histological features among the diverse histologic patterns of GBM, we performed a blinded assessment of the histology of GBMs of 77 patients ≤30 years old at the time of biopsy. The tumors were of the following molecular subtypes: IDH (n = 12), H3 K27M (n = 25), H3 G34R (n = 12), or no IDH/H3 mutations (n = 28). Of IDH-mutated cases, 75% had microcystic features or gemistocytic tumor cells. K27 GBMs had higher cell densities and pronounced nuclear pleomorphism, with 28% harboring tumor giant cells. All G34 GBMs had variable extents of a poorly differentiated/primitive neuroectodermal tumor-like morphology. GBMs without IDH/H3 mutations had foci of epitheliod-appearing cells. Thus, molecular GBM subgroups are associated with distinct histological patterns, suggesting that morphological features reflect the specific underlying molecular genetic abnormalities.
    Keywords: G34r ; Glioblastoma ; H3 ; Histology ; Idh1 ; K27m ; Molecular Subgroups.;
    ISSN: 0022-3069
    E-ISSN: 15546578
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