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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2014, Vol. 16(suppl3), pp.iii16-iii16
    Description: BACKGROUND: Ependymomas are common childhood brain tumors that occur throughout the nervous system, but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. METHODS: We undertook genetic, and epigenetic studies of a series of childhood posterior fossa ependymomas. RESULTS: Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic SNVs. While devoid of recurrent SNVs and focal copy number aberrations, poor prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges exclusively on targets of the polycomb repressor complex 2 (PRC2) that represses expression of differentiation genes through tri-methylation of H3K27. CIMP-positive (CIMP+) hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. CONCLUSIONS: We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically de-regulated but genetically bland. SECONDARY CATEGORY: n/a.
    Keywords: Pediatrics ; Chemotherapy ; Prognosis ; Survival ; Hindbrain ; Cpg Islands ; Children ; Mutation Rates ; Copy Number ; Brain Tumors ; Differentiation ; Malignancy ; Cytotoxicity ; Epigenetics ; Surgery ; DNA Methylation ; Methylation ; Drugs ; Gene Silencing ; Neurology & Neuropathology;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    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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  • 3
    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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  • 4
    Language: English
    In: Cancer, 15 March 2004, Vol.100(6), pp.1230-1237
    Description: BACKGROUND: Ependymomas account for 3-5% of all intracranial malignancies and occur most often in children and young adults. These neoplasms continue to generate considerable controversy with regard to their rational clinical management. It has been shown that the histologic classification of ependymoma is a significant predictor of clinical outcome in patients with ependymoma.METHODS: Ependymomas from 258 patients who underwent microsurgery at a single institution were evaluated histologically to elucidate the prognostic utility of a recently proposed grading scheme. Pathologic and clinical data then were compared using univariate and multivariate analyses.RESULTS: Increasing grade of ependymoma malignancy was found to be associated strongly and independently with worse clinical outcomes in terms of both event-free survival and overall survival. The effect of radiotherapy also was found to be related to histologic grade and was more beneficial for patients who had anaplastic ependymomas and had undergone complete tumor removal.CONCLUSIONS: The application of a uniform diagnostic criteria for grading ependymomas highlighted the key role of tumor histology in clinical outcome in a cohort of patients who were treated in the microsurgical era. The recently proposed grading scheme is likely to be practically useful, reproducible, and clinically applicable.
    Keywords: Ependymoma ; Histology ; Malignancy Grade ; Prognosis ; Radiotherapy
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2010, Vol.16(12), pp.3240-52
    Description: Medulloblastomas are the most common malignant brain tumors in childhood. Survivors suffer from high morbidity because of therapy-related side effects. Thus, therapies targeting tumors in a specific manner with small molecules such as histone deacetylase (HDAC) inhibitors are urgently warranted. This study investigated the expression levels of individual human HDAC family members in primary medulloblastoma samples, their potential as risk stratification markers, and their roles in tumor cell growth. Gene expression arrays were used to screen for HDAC1 through HDAC11. Using quantitative real time reverse transcriptase-PCR and immunohistochemistry, we studied the expression of HDAC5 and HDAC9 in primary medulloblastoma samples. In addition, we conducted functional studies using siRNA-mediated knockdown of HDAC5 and HDAC9 in medulloblastoma cells. HDAC5 and HDAC9 showed the highest expression in prognostically poor subgroups. This finding was validated in an independent set of medulloblastoma samples. High HDAC5 and HDAC9 expression was significantly associated with poor overall survival, with high HDAC5 and HDAC9 expression posing an independent risk factor. Immunohistochemistry revealed a strong expression of HDAC5 and HDAC9 proteins in most of all primary medulloblastomas investigated. siRNA-mediated knockdown of HDAC5 or HDAC9 in medulloblastoma cells resulted in decreased cell growth and cell viability. HDAC5 and HDAC9 are significantly upregulated in high-risk medulloblastoma in comparison with low-risk medulloblastoma, and their expression is associated with poor survival. Thus, HDAC5 and HDAC9 may be valuable markers for risk stratification. Because our functional studies point toward a role in medulloblastoma cell growth, HDAC5 and HDAC9 may potentially be novel drug targets.
    Keywords: Biomarkers, Tumor -- Metabolism ; Brain Neoplasms -- Metabolism ; Histone Deacetylases -- Metabolism ; Medulloblastoma -- Metabolism ; Repressor Proteins -- Metabolism
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    Language: English
    In: Acta Neuropathologica, 2013, Vol.126(3), pp.443-451
    Description: Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked ( ATRX ) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients ( n  = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p  = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis.
    Keywords: ATRX ; IDH ; 1p/19q ; Anaplastic glioma ; MGMT
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 7
    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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  • 8
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(6), p.e0178351
    Description: Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths.This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    In: Neuropathology and Applied Neurobiology, October 2013, Vol.39(6), pp.693-705
    Description: Byline: C. Colin, L. Padovani, C. Chappe, S. Mercurio, D. Scavarda, A. Loundou, F. Frassineti, N. Andre, C. Bouvier, A. Korshunov, G. Lena, D. Figarella-Branger Keywords: biological prognostic factors; clinicopathological prognostic factors; KIAA1549:BRAF fusion; pilocytic astrocytoma; pilomyxoid variant Background Pilocytic astrocytomas (PAs) are characterized by an excellent prognosis although several factors of adverse outcome have been reported. The mitogen-activated protein kinase pathway plays a major role in their tumorigenesis. Aim To report a series of 148 PAs in children to define clinicopathological and biological prognostic factors. Methods Clinical data were collected from patient files and mail inquiry. Pathological specimens were centrally reviewed. The three major KIAA1549:BRAF fusion subtypes were analysed by reverse transcription - polymerase chain reaction (RT-PCR) in a subset of 47 frozen cases and by fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue in 23 cases. Tumour location, age at surgery, extent of surgical removal, histological subtype and KIAA1549:BRAF fusion by RT-PCR were searched for prognostic significance. Results Pilomyxoid astrocytoma (PMA) and the hypothalamo-chiasmatic (H/C) location were associated with a worse prognosis [P 0.001 for overall survival (OS) and P=0.001 for progression-free survival (PFS)]. Patients who underwent complete surgical excision had a better OS (P=0.004) and a longer PFS (P 0.001) than the others. Age was also a strong prognostic factor for OS but not for PFS. Infants ( 1 year) and young children ( 3 years) had a much worse outcome than the others (P 0.001 and P=0.004 respectively). KIAA1549:BRAF fusion status was not predictive of outcome. Conclusion This study highlights the good prognostic factors of PAs but H/C PA remains a subgroup with dismal prognosis associated with young age, PMA variant and incomplete surgery. Search for KIAA1549:BRAF fusion in tumours with PA pattern is recommended even though the prognostic impact is still unclear. Article Note: These two authors have equally contributed to this work.
    Keywords: Biological Prognostic Factors ; Clinicopathological Prognostic Factors ; : Fusion ; Pilocytic Astrocytoma ; Pilomyxoid Variant
    ISSN: 0305-1846
    E-ISSN: 1365-2990
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  • 10
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 August 2015, Vol.21(16), pp.3750-8
    Description: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
    Keywords: DNA Copy Number Variations -- Genetics ; Ependymoma -- Genetics ; Spinal Neoplasms -- Genetics ; Transcriptome -- Genetics
    ISSN: 1078-0432
    E-ISSN: 15573265
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