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  • Brain Tumors
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  • 1
    Language: English
    In: The Journal of clinical investigation, April 2011, Vol.121(4), pp.1344-8
    Description: Pilocytic astrocytoma (PA) is the most common type of primary brain tumor in children and the second most frequent cancer in childhood. Children with incompletely resected PA represent a clinically challenging patient cohort for whom conventional adjuvant therapies are only moderately effective. This has produced high clinical demand for testing of new molecularly targeted treatments. However, the development of new therapeutics for PA has been hampered by the lack of an adequate in vivo tumor model. Recent studies have identified activation of MAPK signaling, mainly by oncogenic BRAF activation, as a hallmark genetic event in the pathogenesis of human PA. Using in vivo retroviral somatic gene transfer into mouse neural progenitor cells, we have shown here that ectopic expression of the activated BRAF kinase domain is sufficient to induce PA in mice. Further in vitro analyses demonstrated that overexpression of activated BRAF led to increased proliferation of primary mouse astrocytes that could be inhibited by treatment with the kinase inhibitor sorafenib. Our in vivo model for PA shows that the activated BRAF kinase domain is sufficient to induce PA and highlights its role as a potential therapeutic target.
    Keywords: Astrocytoma -- Etiology ; Brain Neoplasms -- Etiology ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00219738
    E-ISSN: 1558-8238
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  • 2
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.2696-2696
    Description: CNS-primitive neuroectodermal tumors (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Histological diagnosis is complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other CNS tumors. To investigate this we have analyzed 323 fresh-frozen or paraffin-embedded institutionally diagnosed CNS-PNETs using DNA methylation and expression arrays. Data were compared to 211 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities.
    Keywords: Brain Tumors ; Differentiation ; Central Nervous System ; Data Processing ; Classification ; Pediatrics ; Adolescence ; DNA Methylation ; Nervous System Diseases ; Children ; Neurology & Neuropathology;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    In: Nature, 2012, Vol.482(7386), p.529
    Description: Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord (1). Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system (2). The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour (3,4). Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.
    Keywords: Gene Mutation -- Health Aspects ; Gene Mutation -- Research ; Medulloblastoma -- Development And Progression ; Medulloblastoma -- Genetic Aspects ; Medulloblastoma -- Risk Factors ; Medulloblastoma -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    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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  • 5
    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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  • 6
    Language: English
    In: Acta Neuropathologica, 2011, Vol.121(2), pp.283-285
    Description: Byline: Marco Gessi (1), Stefan Pfister (2,3), Volkmar H. Hans (4), Andrey Korshunov (5,6), Torsten Pietsch (1) Author Affiliation: (1) Institute of Neuropathology, University of Bonn Medical Center, Sigmund-Freud Strasse 25, 53127, Bonn, Germany (2) Department of Pediatric Haematology and Oncology, University of Heidelberg, Heidelberg, Germany (3) Molecular Genetics of Pediatric Brain Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany (4) Institute of Neuropathology, Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany (5) Institute of Neuropathology, University of Heidelberg, Heidelberg, Germany (6) Clinical Cooperation Unit German Cancer Research Center (DKFZ), Heidelberg, Germany Article History: Registration Date: 06/11/2010 Received Date: 12/10/2010 Accepted Date: 06/11/2010 Online Date: 18/11/2010
    Keywords: Cancer Research ; Genetic Research ; Molecular Genetics ; Brain Tumors ; Universities And Colleges;
    ISSN: 0001-6322
    E-ISSN: 1432-0533
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  • 7
    In: Nature Reviews Neurology, 2012, Vol.8(6), p.340
    Description: Medulloblastoma, the most common malignant paediatric brain tumour, is currently diagnosed and stratified using a combination of clinical and demographic variables. Recent transcriptomic approaches have demonstrated that the histological entity known as medulloblastoma is comprised of multiple clinically and molecularly distinct subgroups. The current consensus is that four defined subgroups of medulloblastoma exist: WNT, SHH, Group 3, and Group 4. Each subgroup probably contains at least one additional level of hierarchy, with some evidence for multiple subtypes within each subgroup. The demographic and clinical differences between the subgroups present immediate and pressing questions to be addressed in the next round of clinical trials for patients with medulloblastoma. Many of the genetically defined targets for rational medulloblastoma therapies are unique to a given subgroup, suggesting the need for subgroup-specific trials of novel therapies. The development of practical, robust and widely accepted subgroup biomarkers that are amenable to the conditions of a prospective clinical trial is, therefore, an urgent need for the paediatric neuro-oncology community. In this Review, we discuss the clinical implications of molecular subgrouping in medulloblastoma, highlighting how these subgroups are transitioning from a research topic in the laboratory to a clinically relevant topic with important implications for patient care. Northcott, P. A. et al. Nat. Rev. Neurol. 8, 340-351 (2012); published online 8 May 2012; doi: 10.1038/nrneurol.2012.78
    Keywords: Medulloblastoma -- Diagnosis ; Medulloblastoma -- Care And Treatment ; Medulloblastoma -- Genetic Aspects ; Medulloblastoma -- Research ; Biological Markers -- Research;
    ISSN: 1759-4758
    E-ISSN: 17594766
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  • 8
    In: Archives of Pathology & Laboratory Medicine, Jan, 2002, Vol.126(1), p.42(7)
    Description: * Objective.--To investigate immunoexpression of 2 cyclin-dependent kinase inhibitors, p18INK4C (p18) and p14ARF (p14), in oligodendrogliomas and to evaluate the possible association with tumor grade and clinical outcome. Design.--One hundred seventeen specially selected cases of cerebral oligodendrogliomas were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to p18INK4C (118.2) and p14ARF (FL-132) proteins. A computerized color image analyzer was used to count immunostained nuclei. Results.--p18 nuclear immunoexpression was found in 57 (49%) of the oligodendrogliomas we studied, p18 immunoreactivity exhibited a clear tendency to elevate with increasing tumor grade, and the mean p18 labeling index was 9.7% for low-grade (World Health Organization [WHO] grade II) and 19.2% for high-grade (WHO III) tumors. p14-immunopositive nuclei were found in 87 (74%) tumors, and p14 immunoreactivity showed no correlation with oligodendroglioma histological malignancy. Survival times were significantly reduced for p18-positive tumors, and risk of death was independently associated with p18 expression (hazard ratio = 2.48; P = .01). There was no difference in survival times in patients with or without p14 immunoreactivity. Conclusions.--p18 protein expression is closely associated with malignant oligodendrogliomas and worse clinical outcome. It seems unlikely that p14 immunohistochemistry will be of value in assessing individual prognosis for these tumors. (Arch Pathol Lab Med. 2002;126;42-48)
    Keywords: Gliomas -- Analysis ; Brain Tumors -- Diagnosis ; Cancer Genetics -- Genetic Aspects
    ISSN: 1543-2165
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  • 9
    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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  • 10
    Language: English
    In: Nature medicine, November 2018, Vol.24(11), pp.1752-1761
    Description: Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children's Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and seven cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.
    Keywords: Biological Specimen Banks ; Immunohistochemistry ; Brain Neoplasms -- Pathology ; Xenograft Model Antitumor Assays -- Methods
    ISSN: 10788956
    E-ISSN: 1546-170X
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