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Berlin Brandenburg

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  • Oxford Journals (Oxford University Press)  (73)
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  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl3), pp.iii21-iii21
    Description: Childhood CNS primitive neuro-ectodermal tumors (CNS-PNETs; WHO °IV) are poorly differentiated embryonal tumors with early onset and aggressive clinical behavior. Histological diagnosis can be complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other childhood CNS tumors. To investigate this we have analyzed 254 fresh-frozen or paraffin-embedded CNS-PNET samples using DNA methylation (n = 254) and expression (n = 76) arrays. (Epi-)genetic profiles of CNS-PNETs were compared to those of 〉5000 other childhood brain tumors including embryonal, astrocytic, and ependymal entities, and their respective molecular subgroups. DNA methylation and gene expression profiles showed a clear segregation of pediatric brain tumors by histological entities and molecular subgroups. Interestingly, CNS-PNET profiles showed a significant overlap with various well-defined entities, including AT/RT, ETMR, high-grade glioma, medulloblastoma, and ependymoma. When screening CNS-PNETs with profiles highly resembling other entities, hallmark genetic alterations of these, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, or mutations/deletions of the SMARCB1 locus, were frequently detected. Also, established protein markers, such as INI-1, LIN28A, and OLIG2, confirmed the reclassification of these CNS-PNETs. Strikingly, a subset (∼25%) of CNS-PNETs, which could not be reclassified, segregated into 3-4 distinct molecular subgroups, each with its own characteristic pattern of DNA-methylation, copy number aberrations, gene expression, and mutations. The correct classification of CNS-PNETs remains challenging. Based on DNA methylation, many cases can be reliably re-classified, indicating that a significant proportion of CNS-PNETs may comprise a variety of other tumor subtypes. These findings suggest that the use of established and novel subgroup markers is needed in order to assist the histopathological evaluation of these tumors. In addition, we have identified a number of true CNS-PNET subtypes and are currently analyzing them in more detail in order to elucidate the genetics of these distinct groups.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    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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  • 3
    In: Neuro-Oncology, 2015, Vol. 17(suppl5), pp.v143-v143
    Description: Glioblastoma is a malignant brain tumor that occurs in all age groups and corresponds to WHO°IV. Based on genetics, global gene expression, and methylation patterns, glioblastoma may be categorized in different molecular subgroups. Among these subgroups “IDH” glioblastomas, which carry mutations within IDH1 or IDH2, as well as the “K27” and “G34” subgroups, which are characterized by distinct mutations within the H3F3A gene, can be clearly identified by sequencing methods and are particularly often found in younger patients below 30 years of age. We aimed to analyze the histomorphology of glioblastomas found in patients ≤30 years with the following assigned molecular subgroups: IDH (n = 12), H3F3A K27M (n = 21), H3F3A G34R (n = 12) or no IDH/H3F3A mutations (n = 24). Assessment of histomorphological characteristics was done blinded. IDH mutated cases displayed moderate cell densities and nuclear pleomorphism, showed an astroglial morphology and often harbored microcystic features or gemistocytic tumor cells. H3F3A K27M mutated cases more often showed necroses and displayed higher cell densities and pronounced nuclear pleomorphism. A fraction of these cases was additionally characterized by tumor giant cells. Glioblastoma cases carrying H3F3A G34R mutations predominantly displayed an undifferentiated/PNET-like morphology with densely packed cells and high nuclear pleomorphism. Tumor cell foci with epithelial appearance were specifically found in glioblastoma cases without IDH or H3F3A mutations. Moreover, a fraction of glioblastoma cases without IDH/H3F3A mutations exhibited tumor giant cells. Thus, molecular glioblastoma subgroups are characterized by distinct histomorphological features that can be detected by routine histology. Both IDH mutated cases and H3F3A G34R glioblastoma cases presented histomorphologically as a quite homogenous group. In contrast, H3F3A K27M cases and glioblastomas without IDH/H3F3A mutations displayed disparities of histomorphology, that might imply a more heterogeneous molecular picture. Our study underlines the diversity of glioblastoma and suggests that distinct morphological features reflect the underlying molecular characteristics.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 4
    In: Neuro-Oncology, 2014, Vol. 16(suppl3), pp.iii23-iii23
    Description: BACKGROUND: According to the current WHO classification of CNS tumors, childhood CNS primitive neuro-ectodermal tumors (CNS-PNETs; WHO °IV) are poorly differentiated embryonal tumors with early onset and aggressive clinical behavior. Histological diagnosis can be complicated by morphological heterogeneity and divergent differentiation. Recent studies suggest the existence of molecular subgroups of CNS-PNETs sharing biological characteristics with other childhood CNS tumors. Here, we aimed at a comprehensive molecular characterization of CNS-PNETs and compared our results to profiles of other brain tumor entities in order to define the biological nature of tumors diagnosed as CNS-PNETs. METHODS: A collection of 211 fresh-frozen or paraffin-embedded tumor samples with an institutional diagnosis “CNS-PNET” was profiled for genome-wide DNA methylation patterns and copy-number alterations, complemented by transcriptomic profiling of a subset (n = 71). (Epi-)genetic profiles of CNS-PNETs were compared to those of 〉3000 other childhood brain tumors including embryonal, astrocytic, and ependymal entities, and their respective molecular subgroups. We screened selected groups of tumors for recurrent mutations and expression of established molecular markers. RESULTS: DNA methylation and gene expression profiles showed a clear segregation of pediatric brain tumors by histological entities and molecular subgroups. Interestingly, CNS-PNET profiles showed a significant overlap with various well-defined entities, including AT/RT, ETMR, high-grade glioma, medulloblastoma, and ependymoma. When screening CNS-PNETs with profiles highly resembling other entities, hallmark genetic alterations of these, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, or mutations/deletions of the SMARCB1 locus, were frequently detected. Also, established protein markers, such as INI-1, LIN28A, and OLIG2, confirmed the reclassification of these CNS-PNETs. Strikingly, a subset (∼25%) of CNS-PNETs which could not be reclassified segregated into 3-4 distinct molecular subgroups, each with its own characteristic pattern of copy-number aberrations, DNA-methylation and gene expression. Currently, whole genome and RNA-sequencing of these distinct subgroups of CNS-PNETs is ongoing to reveal their underlying genetics. CONCLUSIONS: The correct classification of CNS-PNETs remains challenging. Based on the detection of recurrent genetic aberrations, many cases can be reliably re-classified, indicating that a significant proportion of CNS-PNETs may comprise a variety of other tumor subtypes. These findings suggest that the use of established and novel subgroups markers is needed in order to assist the histopathological evaluation of these tumors. In addition, we have identified a number of true CNS-PNET subtypes and are currently analyzing them in more detail in order to elucidate the genetics of these distinct groups. SECONDARY CATEGORY: Tumor Biology.
    Keywords: Genomes ; Central Nervous System ; Reclassification ; Pediatrics ; Aggressive Behavior ; Oncology ; Olig2 Protein ; Children ; Brain Tumors ; Gene Expression ; Differentiation ; Gene Deletion ; DNA Methylation ; Medulloblastoma ; Nervous System Diseases ; Glioma ; Mutation ; Neurology & Neuropathology;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 5
    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii143-iii143
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 6
    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii11-iii11
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 7
    In: Neuro-Oncology, 2015, Vol. 17(suppl5), pp.v141-v141
    Description: CNS-primitive neuroectodermal tumors (CNS-PNETs) are poorly differentiated embryonal tumors with early onset and aggressive clinical behavior. 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 301 fresh-frozen or paraffin-embedded CNS-PNET samples using DNA methylation (n = 301) and expression (n = 76) arrays. (Epi-)genetic profiles of CNS-PNETs were compared to 〉200 reference cases of other pediatric and adult brain tumors representing more than 20 well-known entities. DNA methylation and gene expression patterns segregated brain tumors by histological entities and molecular subgroups. Solely, CNS-PNET profiles showed a significant overlap with various well-defined entities, including AT/RT, ETMR, high-grade glioma, medulloblastoma, ependymoma, and others. When screening CNS-PNETs with profiles highly resembling other entities, hallmark genetic alterations of these, such as amplification of 19q13.42, mutations in IDH1 or H3F3A, or mutations/deletions of the SMARCB1 locus, were frequently detected. Also, established protein markers, such as INI-1, LIN28A, and OLIG2, confirmed the reclassification of these CNS-PNETs. Strikingly, a subset (∼25%) of CNS-PNETs, which could not be reclassified, segregated into at least five distinct molecular subgroups, each with its own characteristic pattern of DNA-methylation, copy number aberrations, gene expression, and recurrent mutations. Extending our clustering cohort to include larger series of non CNS PNET tumours, we identified additional brain tumors from various entities to resemble DNA methylation and mutation patterns of these five new molecular subgroups. The correct classification of CNS-PNETs based solely on histology remains challenging. The majority of cases can reliably be reclassified using molecular markers, indicating that a significant proportion of CNS-PNETs represents a variety of other brain tumor subtypes. The remaining CNS PNETs comprise five novel tumour groups with distinct molecular features that overlap with tumors previously diagnosed as non PNETs.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    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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  • 9
    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii9-iii9
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 10
    In: Neuro-Oncology, 2016, Vol. 18(suppl4), pp.iv13-iv14
    Description: Astroblastoma is a rare brain tumor mainly defined by histological features of perivascular orientated glial cells with abundant eosinophilic cytoplasm and the presence of pericellular and vascular hyalinization as well as formation of pseudo-papillae. Molecular studies on this entity are scarce. Clinical courses range from benign to highly malignant. Recurrent MN1 gene fusions have recently been identified in a subset of CNS-PNET with overrepresentation of astroblastic histological features (designated CNS high-grade neuroepithelial tumor with MN1 alteration / HGNET- MN1 ). We here analyzed a large retrospective series of 37 tumors with histological features of astroblastoma by genome-wide DNA methylation profiling, copy number analysis, and targeted sequencing in a subset of cases. Unsupervised hierarchical clustering analysis of DNA methylation data together with a large number of established CNS tumor classes assigned astroblastomas to several molecular classes. The largest number shows high similarity to the HGNET MN1 group (20/37; 54% of cases). Remaining tumors molecularly resemble various ependymoma subgroups (4/37; 11%), glioblastoma subgroups (3/37; 8%), pleomorphic xanthoastrocytoma (3/38; 8%), CNS highgrade neuroepithelial tumor with BCOR alteration (2/37; 5%), or are non-classifiable (5/37; 14%). Histologically, tumors from the HGNET- MN1 group display more homogenous astroblastic features than the remaining fraction. Available clinical data of this group confirms female predominance, frequent superficial location, and may indicate a better prognosis compared to non-HGNET- MN1 CNS tumors with astroblastic features.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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