Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • CHILDREN  (9)
  • 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
    Signatur Availability
    BibTip Others were also interested in ...
  • 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
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    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
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    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
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    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
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    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
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; IN-VIVO ; TUMORS ; MUTATIONS ; DUPLICATION ; CENTRAL-NERVOUS-SYSTEM ; LOW-GRADE ASTROCYTOMAS ; CHILDREN ; CHILDHOOD ; PEDIATRIC GLIOMAS ; BRAF FUSION GENE ; MAMMARY TUMORIGENESIS
    Abstract: Purpose: Oncogenic BRAF/Ras or NF1 loss can potentially trigger oncogene-induced senescence (OIS) through activation of the mitogen-activated protein kinase (MAPK) pathway. Somatic genetic abnormalities affecting this pathway occur in the majority of pilocytic astrocytomas (PA), the most prevalent brain neoplasm in children. We investigated whether OIS is induced in PA. Experimental Design: We tested expression of established senescence markers in three independent cohorts of sporadic PA. We also assessed for OIS in vitro, using forced expression of wild-type and V600E-mutant BRAF in two astrocytic cell lines: human telomerase reverse transcriptase (hTERT)-immortalized astrocytes and fetal astrocytes. Results: Our results indicate that PAs are senescent as evidenced by marked senescence-associated acidic beta-galactosidase activity, low KI-67 index, and induction of p16(INK4a) but not p53 in the majority of 52 PA samples (46 of 52; 88.5%). Overexpression of a number of senescence-associated genes [CDKN2A (p16), CDKN1A (p21), CEBPB, GADD45A, and IGFBP7] was shown at the mRNA level in two independent PA tumor series. In vitro, sustained activation of wild-type or mutant BRAF induced OIS in both astrocytic cell lines. Loss of p16(INK4a) in immortalized astrocytes abrogated OIS, indicative of the role of this pathway in mediating this phenomenon in astrocytes. OIS is a mechanism of tumor suppression that restricts the progression of benign tumors. We show that it is triggered in PAs through p16(INK4a) pathway induction following aberrant MAPK activation. Conclusions: OIS may account for the slow growth pattern in PA, the lack of progression to higher-grade astrocytomas, and the high overall survival of affected patients.
    Type of Publication: Journal article published
    PubMed ID: 21610151
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: CANCER ; EXPRESSION ; GROWTH ; IN-VITRO ; radiotherapy ; TUMOR-CELLS ; PATHWAY ; GENE ; GENE-EXPRESSION ; TUMORS ; LINES ; radiation ; IMPACT ; CELL-LINES ; CENTRAL-NERVOUS-SYSTEM ; CHILDREN ; cell lines ; PTEN ; HOMOLOGOUS RECOMBINATION ; DOUBLE-STRAND BREAKS ; BRAIN-TUMORS ; GLIOMA ; ependymoma ; medulloblastoma ; pediatric ; CELL BIOLOGY ; PARP
    Abstract: Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy. Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.4 to 8.4 microM, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome.
    Type of Publication: Journal article published
    PubMed ID: 22184287
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Keywords: RESOLUTION ; MUTATIONS ; DUPLICATION ; LOW-GRADE ASTROCYTOMAS ; CHILDREN ; GLIOMAS ; FUSION GENE ; senescence ; MAPK PATHWAY ACTIVATION ; MAJORITY
    Abstract: Pilocytic astrocytomas (PAs) are the most common brain tumors in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen-activated protein kinase pathway, but little else is known about their development. To map the global DNA methylation profiles of these tumors, we analyzed 62 PAs and 7 normal cerebellum samples using Illumina 450K microarrays. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups, including NR2E1 and EN2. Integration with transcriptome microarray data highlighted significant expression differences, which were unexpectedly associated with a strong positive correlation between methylation and expression. Differentially methylated probes were often identified within the gene body and/or regions up- or downstream of the gene, rather than at the transcription start site. We also identified a large number of differentially methylated genes between cerebellar PAs and normal cerebellum, which were again enriched for developmental genes. In addition, we found a significant association between differentially methylated genes and SUZ12 binding sites, indicating potential disruption of the polycomb repressor complex 2 (PRC2). Taken together, these data suggest that PA from different locations in the brain may arise from region-specific cells of origin, and highlight the potential disruption of key developmental regulators during tumorigenesis. These findings have implications for future basic research and clinical trials, as therapeutic targets and drug sensitivity may differ according to tumor location.
    Type of Publication: Journal article published
    PubMed ID: 23660940
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...