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  • DKFZ Publication Database  (26)
  • TUMORS  (13)
  • MUTATIONS  (10)
  • MYC  (7)
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  • DKFZ Publication Database  (26)
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: PATHWAY ; ACTIVATION ; MUTATIONS ; BRAF ; IDH1 ; Diffuse astrocytoma ; IDH2 ; Pilocytic astrocytoma
    Abstract: Separation of pilocytic astrocytoma from diffuse astrocytomas frequently poses problems mostly related to small sample size. Precise classification and grading are essential due to different therapeutic strategies prompted by diagnoses of pilocytic astrocytoma WHO grade I, diffuse astrocytomas WHO grade II or anaplastic astrocytoma WHO grade III. Recently, genomic aberrations with a high specificity for distinct glioma entities have been described. Pilocytic astrocytomas carry a duplication at chromosome band 7q34 containing a BRAF-KIAA1549 gene fusion in the majority of cases. IDH1 mutations are observed very frequently in adult astrocytomas and IDH2 mutations have been reported in some astrocytomas. We examined a series of 120 astrocytomas including 70 pilocytic astrocytomas WHO grade I and 50 diffuse astrocytomas WHO grade II for both, BRAF-KIAA1549 fusion with a newly developed FISH assay and mutations in IDH1 and IDH2 by direct sequencing. Pilocytic astrocytomas contained the BRAF fusion in 49 cases (70%) but neither IDH1 nor IDH2 mutations. Astrocytomas WHO grade II exhibited IDH1 mutations in 38 cases (76%) but neither IDH2 mutations nor BRAF fusions. Thus, combined molecular analysis of BRAF and IDH1 is a sensitive and highly specific approach to separate pilocytic astrocytoma from diffuse astrocytoma.
    Type of Publication: Journal article published
    PubMed ID: 19543740
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  • 4
    Keywords: GENE ; TUMORS ; MECHANISM ; MUTATION ; DUPLICATION ; CENTRAL-NERVOUS-SYSTEM ; LOW-GRADE ASTROCYTOMAS ; GLIOMAS ; B-RAF ; neurofibromatosis type 1 ; Pilocytic astrocytoma ; MAPK PATHWAY ; MAPK PATHWAY ACTIVATION ; insertion mutagenesis
    Abstract: Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated Ras/Raf/MEK/ERK signaling. Common genetic lesions observed in PA, which are linked to aberrant ERK pathway activity include either NF1 inactivation, KRAS or BRAF gain-of-function mutations. In order to investigate the mutation spectrum within the proto-oncogene encoding the Ser/Thr-kinase B-Raf in more detail, we analyzed 64 primary tumor samples from children with PA including two patients with neurofibromatosis type 1 (NF1). The well-known BRAF(V600E) mutation was found in 6/64 (9.38%) of our samples. For the first time, we report concomitant presence of a somatic BRAF(V600E) mutation in an NF1 patient indicating that more than one Ras/ERK pathway component can be affected in PA. Furthermore, 2/64 (3.13%) of our samples carried a 3-bp insertion in BRAF resulting in the duplication of threonine 599. This conserved residue is located within the activation segment and, if phosphorylated in a Ras-dependent manner, plays a key role in Raf activation. Here, we demonstrate that this mutant (B-Raf(insT)) and another B-Raf mutant, which carries two additional threonine residues at this position, display an in vitro kinase activity and cellular MEK/ERK activation potential comparable to those of B-Raf(V600E). Notably, replacement of threonines by valine residues had similar effects on B-Raf activity suggesting that the distortion of the peptide backbone by additional amino acids rather than the insertion of additional, potential phosphorylation sites destabilizes the inactive conformation of the kinase domain. We also demonstrate that B-Raf(insT) and B-Raf(V600E), but not B-Raf(wt), provoke drastic morphological alterations in human astrocytes.
    Type of Publication: Journal article published
    PubMed ID: 21190184
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  • 5
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; GENES ; PROTEIN ; transcription ; TRANSCRIPTION FACTOR ; IDENTIFICATION ; PROMOTER ; chemotherapy ; MUTATIONS ; LOCALIZATION ; METHYLATION ; BRAIN-TUMORS ; ACUTE MYELOID-LEUKEMIA ; INTRACRANIAL EPENDYMOMAS ; MDS1/EVI1
    Abstract: Purpose: Ependymomas are glial tumors of presumably radial glial origin that share morphologic similarities with ependymal cells. The molecular genetics of ependymomas of supratentorial, infratentorial, and spinal location is heterogeneous. We aimed at identifying pathways operative in the development of infratentorial ependymomas. Experimental Design: To do so, gene expression profiles of tumor cells laser microdissected from infratentorial ependymomas (n = 15) were compared with that of nonneoplastic ependymal cells laser microdissected from autopsy tissue (n = 7). Results: Among 31 genes significantly overexpressed (〉5-fold) in ependymomas, transcription factor EVI1 (ecotropic viral integration site 1) showed the highest overexpression (35-fold). Evi-1 protein expression could be confirmed in formalin-fixed, paraffin-embedded samples of 26 of 28 infratentorial ependymomas but only in 7 of 47 nonependymal glial tumors (P 〈 0.001). Furthermore, MDS1/EVI1 fusion transcripts were detectable in 17 of 28 infratentorial ependymomas and significantly correlated with MGMT (O6-methylguanine-DNA-methyltransferase) promoter hypermethylation (P 〈 0.05). In primary infratentorial ependymoma cells, transfection with EVI1-specific siRNAs resulted in significant growth inhibition [48 hours: 87% +/- 2% and 74% +/- 10% as compared with control (mean +/- SD; P 〈 0.001)]. The prognostic role of EVI1 could further be validated in an independent cohort of 39 infratentorial and 26 supratentorial ependymomas on the basis of mRNA expression profiling. Although in supratentorial ependymomas EVI1 expression status had no prognostic impact, in infratentorial ependymomas, high EVI1 expression was associated with shorter overall survival and progression-free survival. Conclusions: To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable.
    Type of Publication: Journal article published
    PubMed ID: 21493867
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  • 6
    Keywords: EXPRESSION ; TUMORS ; ABERRATIONS ; METHYLATION ; EMBRYONIC STEM-CELLS ; MULTIFORME ; HIGH-GRADE GLIOMAS ; TELOMERES ; INTEGRATED GENOMIC ANALYSIS ; ATRX
    Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 22286061
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  • 7
    Keywords: CANCER ; PATHWAY ; GENES ; ACTIVATION ; MUTATIONS ; SUBGROUPS ; LANDSCAPE ; TETRAPLOID TUMOR-CELLS ; TBR1
    Abstract: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
    Type of Publication: Journal article published
    PubMed ID: 22832583
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  • 8
    Keywords: proliferation ; TUMORS ; METHYLATION ; CELL-GROWTH ; medulloblastoma ; GLIOBLASTOMA ; MULTIPLE GENES ; DISTINCT SUBGROUPS ; INTRACRANIAL EPENDYMOMA ; DRIVER MUTATIONS
    Abstract: Ependymoma is the third most common pediatric brain tumor, yet because of the paucity of effective therapeutic interventions, 45% of patients remain incurable. Recent transcriptional and copy number profiling of the disease has identified few driver genes and in fact points to a balanced genomic profile. Candidate gene approaches looking at hypermethylated promoters and genome-wide epigenetic arrays suggest that DNA methylation may be critical to ependymoma pathogenesis. This review attempts to highlight existing and emerging evidence implicating the ependymoma epigenome as a key player and that epigenetic modifiers may offer new targeted therapeutic avenues for patients.
    Type of Publication: Journal article published
    PubMed ID: 23432646
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  • 9
    Keywords: CANCER ; GROWTH ; TUMORS ; NERVOUS-SYSTEM ; ADULT ; MOUSE MODELS ; PEDIATRIC MEDULLOBLASTOMA ; HEDGEHOG PATHWAY INHIBITOR ; TERT PROMOTER MUTATIONS ; ITRACONAZOLE
    Abstract: Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children 〉3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
    Type of Publication: Journal article published
    PubMed ID: 24651015
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  • 10
    Keywords: GENE ; NF-KAPPA-B ; MUTATIONS ; CENTRAL-NERVOUS-SYSTEM ; medulloblastoma ; SUBGROUPS ; GLIOBLASTOMA ; CHILDHOOD EPENDYMOMAS ; PEDIATRIC INTRACRANIAL EPENDYMOMAS ; POSTERIOR-FOSSA EPENDYMOMAS
    Abstract: Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
    Type of Publication: Journal article published
    PubMed ID: 25965575
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