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  • 1
    In: Neuro-Oncology, 2016, Vol. 18(7), pp.893-894
    Description: Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: International Journal of Cancer, 15 August 2013, Vol.133(4), pp.908-919
    Description: High levels of the NTRK1/TrkA receptor are expressed in low‐stage neuroblastomas, which are characterized by a good patient prognosis and often undergo spontaneous regression. In addition to apoptosis, tumor‐immune responses might contribute to this regression. We hypothesized that TrkA expression might enhance the immune response to neuroblastomas. Immunohistochemistry on neuroblastoma tissue microarrays confirmed significantly higher lymphocyte infiltration in low‐stage compared with high‐stage tumors. Flow cytometry of human SH‐SY5Y cells stably transfected with cDNA revealed significant upregulation of major histocompatibility complex (MHC) class I complexes on TrkA‐expressing cells. Corresponding to this upregulation, T cell activity and cytoxicity was enhanced in the presence of SY5Y‐TrkA cells or by medium conditioned by them, suggesting the existence of additional soluble factors stimulating the T cell response. Activation of natural killer (NK) cells was only increased in the presence of SY5Y‐TrkA conditioned medium (CM) and not in co‐culture assays, suggesting a dominant inhibitory effect of upregulated MHC class I as the primary NK cell escape mechanism of TrkA‐expressing neuroblastomas. We reanalyzed gene expression data obtained from the cell culture model to identify additional genes involved in the TrkA‐mediated modulation of immune responses. Upregulation of selected target genes in SY5Y‐TrkA cells was confirmed on transcript and protein levels. However, none of the proteins were detected in medium conditioned by SY5Y‐TrkA cells, arguing against these factors as soluble mediators of the TrkA‐induced immune response. We here provide evidence that TrkA expression in neuroblastoma leads to an increased immunogenicity that may contribute to a less malignant phenotype and/or spontaneous regression of neuroblastoma cells. What's new? Elevated expression of neurotrophic tyrosine kinase type 1 receptor (NTRK1, or TrkA) previously was found to be associated with favorable prognosis in neuroblastoma. That effect may be the result of TrkA‐induced enhancement of the immune response toward neuroblastoma cells, as reported here. The findings suggest that TrkA‐associated immune activity might partly explain spontaneous regression of low‐stage neuroblastomas. They also have novel translational implications, among them the possibility for the development of T cell‐based immunotherapy approaches.
    Keywords: Neurotrophin Receptor ; Spontaneous Regression ; Cytotoxic Lymphocytes ; Nk Cells
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: Cell Reports, 26 June 2018, Vol.23(13), pp.3699-3700
    Description: Ozawa et al. present a murine tumor model resembling the most frequent molecular group of human supratentorial ependymoma, ST-EPN-RELA. Their model shows RELA-fusion-based ependymoma tumorigenesis in the forebrain derived from neural stem cells. Ozawa et al. present a murine tumor model resembling the most frequent molecular group of human supratentorial ependymoma, ST-EPN-RELA. Their model shows RELA-fusion-based ependymoma tumorigenesis in the forebrain derived from neural stem cells.
    Keywords: Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 4
    In: Nature, 2017, Vol.553(7686), p.101
    Description: Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 5
    In: Nature, 2018
    Description: Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 6
    Language: English
    In: Journal of Neuro-Oncology, 2016, Vol.128(3), pp.463-471
    Description: Systemic administration of etoposide is effective in treating metastatic, recurrent or refractory brain tumors, but penetration into the cerebrospinal fluid is extremely poor. This study was designed to determine the safety and toxicity profile of intraventricular etoposide administration and was affiliated with the prospective, multicenter, nonblinded, nonrandomized, multi-armed HIT-REZ-97 trial. The study enrolled 68 patients, aged 1.1–34.6 (median age 11 years). Adverse events that could possibly be related to intraventricular etoposide therapy were documented and analyzed. Intraventricular etoposide was simultaneously administered with either oral or intravenous chemotherapy in 426 courses according to three major schedules varying in dosing (0.25–1 mg), frequency of administration (bolus injection, every 12 or 24 h), course duration (5–10 days) and length of interval between courses (2–5 weeks). Potential treatment-related adverse effects included transient headache, seizures, infection of the reservoir, nausea and neuropsychological symptoms. Hematological side effects were not observed. One patient, with history of multiple prior therapies, who received long-term intraventricular and oral etoposide treatment developed acute myeloid leukemia as a secondary malignancy. Overall intraventricular etoposide is well tolerated. The results of this study have warranted a phase II trial to determine the effectiveness of this regimen in disease stages with very limited therapeutic options.
    Keywords: Ependymoma ; Medulloblastoma ; ATRT ; Relapse ; Progression ; Pediatric brain tumors
    ISSN: 0167-594X
    E-ISSN: 1573-7373
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  • 7
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Central Nervous System Neoplasms -- Diagnosis;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 8
    Language: English
    In: Acta neuropathologica communications, 29 May 2013, Vol.1, pp.19
    Description: Medulloblastoma is a leading cause of childhood cancer-related deaths. Current aggressive treatments frequently lead to cognitive and neurological disabilities in survivors. Novel targeted therapies are required to improve outcome in high-risk medulloblastoma patients and quality of life of survivors. Targeting enzymes controlling epigenetic alterations is a promising approach recently bolstered by the identification of mutations in histone demethylating enzymes in medulloblastoma sequencing efforts. Hypomethylation of lysine 4 in histone 3 (H3K4) is also associated with a dismal prognosis for medulloblastoma patients. Functional characterization of important epigenetic key regulators is urgently needed. We examined the role of the H3K4 modifying enzyme, KDM1A, in medulloblastoma, an enzyme also associated with malignant progression in the closely related tumor, neuroblastoma. Re-analysis of gene expression data and immunohistochemistry of tissue microarrays of human medulloblastomas showed strong KDM1A overexpression in the majority of tumors throughout all molecular subgroups. Interestingly, KDM1A knockdown in medulloblastoma cell lines not only induced apoptosis and suppressed proliferation, but also impaired migratory capacity. Further analyses revealed bone morphogenetic protein 2 (BMP2) as a major KDM1A target gene. BMP2 is known to be involved in development and differentiation of granule neuron precursor cells (GNCPs), one potential cell of origin for medulloblastoma. Treating medulloblastoma cells with the specific KDM1A inhibitor, NCL-1, significantly inhibited growth in vitro. We provide the first evidence that a histone demethylase is functionally involved in the regulation of the malignant phenotype of medulloblastoma cells, and lay a foundation for future evaluation of KDM1A-inihibiting therapies in combating medulloblastoma.
    Keywords: Histone Demethylases -- Metabolism ; Medulloblastoma -- Enzymology ; Oxidoreductases, N-Demethylating -- Metabolism
    E-ISSN: 2051-5960
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  • 9
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.SY15-02-SY15-02
    Description: Malignant pediatric brain tumors, including ependymoma, medulloblastoma and atypical teratoidrhabdoid tumors, frequently demonstrate a very quiet genome with very few nonsynonyomous single nucleotide variants or indels and a stable copy number profile. The recent advance of integrative genomics approaches from primary tumor tissue including whole-genome sequencing, RNA sequencing, whole-genome bisulfite sequencing, and ChIP sequencing for core histone marks and important transcription factors and chromatin configuration have enabled the discovery of new tumor-driving pathways and potentially druggable alterations in these cancers with quiet genomes. This knowledge after functional validation in vitro and in vivo provides critical insight in the search for the cell of origin in these tumors, the understanding of underlying pathomechanisms, and the identification of new treatment options.
    Keywords: Brain Mapping ; Histones ; Chromatin ; Pediatrics ; Landscape ; Bisulfite ; Nucleotides ; Cancer ; Copy Number ; Brain Tumors ; Enhancers ; RNA ; Transcription Factors ; Medulloblastoma ; Genomics ; Gene Mapping ; Development & Cell Cycle ; Miscellaneous Oncogenes & Growth Factors;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 10
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.4124-4124
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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