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  • DKFZ Publication Database  (25)
  • Jun  (10)
  • CHILDREN  (9)
  • MYC  (7)
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  • DKFZ Publication Database  (25)
Keywords
  • 1
    Keywords: brain ; tumor ; Germany ; neoplasms ; TOOL ; HYBRIDIZATION ; DIFFERENTIATION ; TUMORS ; MARKER ; BIOLOGY ; IN-SITU ; AMPLIFICATION ; AGE ; ABERRATIONS ; FISH ; CENTRAL-NERVOUS-SYSTEM ; pathology ; CHILDREN ; BEHAVIOR ; CHROMOSOMES ; FEATURES ; brain tumor ; BRAIN-TUMORS ; PRIMITIVE NEUROECTODERMAL TUMORS ; LOCUS ; diagnostic marker ; ABUNDANT NEUROPIL ; TRUE ROSETTES ; 19q13 ; Embryonal brain tumor ; Ependymoblastoma ; ETANTR ; Molecular diagnosis ; WHO classification of CNS tumors
    Abstract: Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors (n = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80-100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior
    Type of Publication: Journal article published
    PubMed ID: 20407781
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  • 2
    Keywords: brain ; tumor ; Germany ; MODEL ; MODELS ; ALGORITHM ; screening ; SYSTEM ; COHORT ; RISK ; HYBRIDIZATION ; TUMORS ; PATIENT ; ACTIVATION ; DNA ; MARKER ; IMPACT ; prognosis ; BIOLOGY ; DELETION ; IN-SITU ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; NUMBER ; ABERRATIONS ; MARKERS ; ONCOGENE ; beta-catenin ; PROGNOSTIC VALUE ; OUTCOMES ; CHILDREN ; ONCOLOGY ; ADULT ; ADULTS ; CHILDHOOD ; brain tumor ; GENOMIC ABERRATIONS ; DNA COPY NUMBER ; medulloblastoma ; methods ; PROGNOSTIC MARKER ; RISK STRATIFICATION ; LOCI ; MYC ; outcome ; TUMOR BIOLOGY ; Genetic ; NUCLEAR BETA-CATENIN ; clinical oncology ; STRATIFICATION
    Abstract: Purpose Medulloblastoma (MB) is the most common malignant brain tumor in children, whereas it rarely presents in adults. We aimed to identify genetic aberrations in 146 adult MBs to evaluate age-dependent differences in tumor biology and adapt age-specific risk stratification models. Methods As a screening set, we studied a cohort of 34 adult MBs by using array-based comparative genomic hybridization comparing molecular results with clinical data. DNA copy number aberrations identified as possible prognostic markers were validated in an independent cohort of 112 adult patients with MB by fluorescent in situ hybridization analysis. Results were compared with the data obtained from 404 pediatric patients with MB. Results CDK6 amplification, 10q loss, and 17q gain are the most powerful prognostic markers in adult MB. Whereas MYC/MYCN oncogene amplifications had a high prognostic value in pediatric MB, these aberrations were rarely observed in adult tumors. Surprisingly, adult MBs with 6q deletion and nuclear beta-catenin activation did not share the excellent prognosis with their pediatric counterparts. Conclusion Adult MB is distinct from pediatric MB in terms of genomic aberrations and their impact on clinical outcomes. Therefore, adult MBs require age-specific risk stratification models. We propose a molecular staging system involving three distinct risk groups based on DNA copy number status of 10q and 17q
    Type of Publication: Journal article published
    PubMed ID: 20479417
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  • 3
    Keywords: INHIBITOR ; Germany ; DISEASE ; RISK ; SITE ; GENE ; GENES ; PROTEIN ; ACTIVATION ; CLEAVAGE ; MUTATION ; genetics ; MUTATIONS ; Jun ; INDIVIDUALS ; heredity ; chronic pancreatitis ; RECOMBINANT ; pancreas ; VARIANT ; ENZYME ; pancreatic ; LOSSES ; odds ratio ; PROTECTS ; HEREDITARY PANCREATITIS ; HUMAN CATIONIC TRYPSINOGEN
    Abstract: Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) 1 and the pancreatic secretory trypsin inhibitor (SPINK1) 2 are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis
    Type of Publication: Journal article published
    PubMed ID: 16699518
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  • 4
    Keywords: EXPRESSION ; COHORT ; DISEASE ; TISSUE ; IDENTIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; chemotherapy ; MUTATIONS ; ABNORMALITIES ; CHILDREN ; IMBALANCES ; PEDIATRIC EPENDYMOMA ; INTRACRANIAL EPENDYMOMA ; CLASS DISCOVERY
    Abstract: Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochennical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymonna tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients
    Type of Publication: Journal article published
    PubMed ID: 21840481
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  • 5
    Keywords: IN-VIVO ; PHASE-I ; GROWTH-FACTOR RECEPTOR ; IDENTIFICATION ; CENTRAL-NERVOUS-SYSTEM ; CHILDREN ; REFRACTORY SOLID TUMORS ; INTRACRANIAL EPENDYMOMA ; INITIATING CELLS ; CHILDHOOD EPENDYMOMAS
    Abstract: Incompletely resectable ependymomas are associated with poor prognosis despite intensive radio- and chemotherapy. Novel treatments have been difficult to develop due to the lack of appropriate models. Here, we report on the generation of a high-risk cytogenetic group 3 and molecular group C ependymoma model (DKFZ-EP1NS) which is based on primary ependymoma cells obtained from a patient with metastatic disease. This model displays stem cell features such as self-renewal capacity, differentiation capacity, and specific marker expression. In vivo transplantation showed high tumorigenic potential of these cells, and xenografts phenotypically recapitulated the original tumor in a niche-dependent manner. DKFZ-EP1NS cells harbor transcriptome plasticity, enabling a shift from a neural stem cell-like program towards a profile of primary ependymoma tumor upon in vivo transplantation. Serial transplantation of DKFZ-EP1NS cells from orthotopic xenografts yielded secondary tumors in half the time compared with the initial transplantation. The cells were resistant to temozolomide, vincristine, and cisplatin, but responded to histone deacetylase inhibitor (HDACi) treatment at therapeutically achievable concentrations. In vitro treatment of DKFZ-EP1NS cells with the HDACi Vorinostat induced neuronal differentiation associated with loss of stem cell-specific properties. In summary, this is the first ependymoma model of a cytogenetic group 3 and molecular subgroup C ependymoma based on a human cell line with stem cell-like properties, which we used to demonstrate the differentiation-inducing therapeutic potential of HDACi.
    Type of Publication: Journal article published
    PubMed ID: 21863243
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  • 6
    Keywords: EXPRESSION ; PATHWAY ; DISEASE ; DISTINCT ; GENE-EXPRESSION ; TUMORS ; prognosis ; MARKERS ; PRECURSORS ; MYCN ; N-MYC ; medulloblastoma ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; MYC ; STRATIFICATION ; PEDIATRIC MEDULLOBLASTOMAS ; SHH pathway ; 10q loss ; MATRIX FACTORIZATION ; MULTICENTER TRIAL HIT91 ; SHH
    Abstract: Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). Twenty-one MYCN-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of MYCN-MBs indicating a biological dichotomy of MYCN-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. In conclusion, we demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor
    Type of Publication: Journal article published
    PubMed ID: 22160402
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  • 7
    Keywords: CELLS ; GENES ; INFECTION ; INDUCTION ; REPLICATION ; NEURONAL DIFFERENTIATION ; MYC ; MEASLES-VIRUS ; RAT MODELS ; SIGNALING CASCADES
    Abstract: Based on extensive pre-clinical studies, the oncolytic parvovirus H-1 (H-1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high-risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H-1PV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non-transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H-1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H-1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H-1PV. H-1PV induced down-regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H-1PV infection. H-1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus.
    Type of Publication: Journal article published
    PubMed ID: 23852775
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  • 8
    Keywords: brain ; tumor ; Germany ; PATHWAY ; PATHWAYS ; DEATH ; DISEASE ; TUMORS ; COMPARATIVE GENOMIC HYBRIDIZATION ; cytogenetics ; MALIGNANCIES ; genetics ; CENTRAL-NERVOUS-SYSTEM ; LOW-GRADE ASTROCYTOMAS ; CHILDREN ; FUTURE ; review ; brain tumor ; BRAIN-TUMORS ; ependymoma ; medulloblastoma ; PRIMITIVE NEUROECTODERMAL TUMORS ; EPIGENETICS ; supratentorial PNET ; PILOCYTIC ASTROCYTOMAS ; Genetic ; Pilocytic astrocytoma ; GENETIC ALTERATIONS ; INTRACRANIAL EPENDYMOMA ; PATHWAY ACTIVATION ; Type ; MAPK PATHWAY ; MEDULLOBLASTOMA SUBTYPES ; Pediatric brain tumors ; Supratentorial primitive neuroectodermal tumor
    Abstract: Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors
    Type of Publication: Journal article published
    PubMed ID: 20425037
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  • 9
    Keywords: tumor ; RISK ; DOWN-REGULATION ; chemotherapy ; p53 ; CHILDREN ; MULTICENTER TRIAL ; CHILDHOOD MEDULLOBLASTOMA ; BETA-CATENIN STATUS ; LI-FRAUMENI ; PEDIATRIC MEDULLOBLASTOMAS
    Abstract: PURPOSE The role of TP53 mutations in the tumorigenesis of sporadic medulloblastoma (MB) and the value of TP53 mutation status as a prognostic marker are not yet definitely elucidated. A recent report identified TP53 mutations in MB as an adverse prognostic marker. Hence, the current study was conducted to validate the prognostic role of TP53 mutation in MB and to understand its contribution to tumorigenesis. METHODS A comprehensive genetic analysis of 310 MB samples was performed by screening for TP53 mutations and further relating the TP53 mutation status to p53 immunostaining, cytogenetic aberrations, and clinical variables. Results Mutation analysis of TP53 revealed mutations in 21 (6.8%) of 310 samples. Germline TP53 mutations were found in two patients with a history suggestive of a hereditary cancer syndrome. TP53 mutation status was not associated with unfavorable prognosis (P = .63) and was not linked to 17p allelic loss but was over-represented in the prognostically favorable WNT subgroup of MB as defined by CTNNB1 mutation (seven of 35 TP53-mutated tumors v 14 of 271 TP53 wild-type tumors; P = .005) and in tumors carrying high-level MYCN amplification (seven of 21 TP53-mutated tumors v 14 of 282 TP53 wild-type tumors; P = .001). CONCLUSION The contradictory results in the recent literature concerning the prognostic value of TP53 mutation might be explained by different frequencies of WNT MBs, different frequencies of patients with Li-Fraumeni syndrome, and different cumulative doses of alkylating drugs applied in these studies.
    Type of Publication: Journal article published
    PubMed ID: 21060032
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  • 10
    Keywords: CANCER ; SYSTEM ; DISTINCT ; GENES ; ADULT ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; PREDICTS ; MYC ; DISEASE RISK
    Abstract: PURPOSE Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors. PATIENTS AND METHODS We combined transcriptome and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were used to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. The prognostic power of follistatin-like 5 (FSTL5) immunopositivity was tested for 235 nonoverlapping medulloblastoma samples on two independent tissue microarrays. Results Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. Stable subgroup separation was achieved by using the 300 transcripts that varied the most. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time polymerase chain reaction. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, more than 50% of non-WNT/non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with a good prognosis who would otherwise be considered intermediate or high-risk on the basis of current molecular subgrouping. CONCLUSION FSTL5 expression denoted a dismal prognosis both within and across medulloblastoma subgroups. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes constitutes a reliable and cost-effective tool for prognostication in future clinical trials of medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 21911727
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