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  • 1
    Publication Date: 2015-10-16
    Description: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peifer, Martin -- Hertwig, Falk -- Roels, Frederik -- Dreidax, Daniel -- Gartlgruber, Moritz -- Menon, Roopika -- Kramer, Andrea -- Roncaioli, Justin L -- Sand, Frederik -- Heuckmann, Johannes M -- Ikram, Fakhera -- Schmidt, Rene -- Ackermann, Sandra -- Engesser, Anne -- Kahlert, Yvonne -- Vogel, Wenzel -- Altmuller, Janine -- Nurnberg, Peter -- Thierry-Mieg, Jean -- Thierry-Mieg, Danielle -- Mariappan, Aruljothi -- Heynck, Stefanie -- Mariotti, Erika -- Henrich, Kai-Oliver -- Gloeckner, Christian -- Bosco, Graziella -- Leuschner, Ivo -- Schweiger, Michal R -- Savelyeva, Larissa -- Watkins, Simon C -- Shao, Chunxuan -- Bell, Emma -- Hofer, Thomas -- Achter, Viktor -- Lang, Ulrich -- Theissen, Jessica -- Volland, Ruth -- Saadati, Maral -- Eggert, Angelika -- de Wilde, Bram -- Berthold, Frank -- Peng, Zhiyu -- Zhao, Chen -- Shi, Leming -- Ortmann, Monika -- Buttner, Reinhard -- Perner, Sven -- Hero, Barbara -- Schramm, Alexander -- Schulte, Johannes H -- Herrmann, Carl -- O'Sullivan, Roderick J -- Westermann, Frank -- Thomas, Roman K -- Fischer, Matthias -- England -- Nature. 2015 Oct 29;526(7575):700-4. doi: 10.1038/nature14980. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. ; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, 50937 Cologne, Germany. ; Division Neuroblastoma Genomics (B087), German Cancer Research Center, 69120 Heidelberg, Germany. ; Department of Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany. ; NEO New Oncology AG, 51105 Cologne, Germany. ; Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute (UPCI), Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA. ; Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany. ; Institute of Biostatistics and Clinical Research, University of Munster, 48149 Munster, Germany. ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. ; Department of Pathology, University of Kiel, 24118 Kiel, Germany. ; Functional Epigenomics, University of Cologne, 50931 Cologne, Germany. ; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Computing Center, University of Cologne, 50931 Cologne, Germany. ; Department of Informatics, University of Cologne, 50931 Cologne, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Pediatric Oncology and Hematology, Charite University Medical Center Berlin, 10117 Berlin, Germany. ; Center for Medical Genetics, Ghent University, 9000 Ghent, Belgium. ; BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083 China. ; Center for Pharmacogenomics and Fudan-Zhangjiang Center for Clinical Genomics, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 201203, China. ; Department of Pathology, University of Cologne, 50937 Cologne, Germany. ; Department of Pediatric Oncology and Hematology, University Children's Hospital, 45147 Essen, Germany. ; German Cancer Consortium (DKTK), 10117 Berlin, Germany. ; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany. ; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466568" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Keywords: MDM2 ; drug resistance ; neuroblastoma ; DNA damage response ; MYCN/c-MYC ; nutlin-3a
    Type of Publication: Journal article published
    PubMed ID: 20557856
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  • 3
    Keywords: PHASE-I ; p53 ; CANCER-THERAPY ; N-MYC ; CYCLE ARREST ; HIGH-RISK NEUROBLASTOMA ; DEPENDENT KINASE 4/6 ; DIRECT TRANSCRIPTIONAL TARGET ; PHARMACOLOGICAL INHIBITION ; PD 0332991
    Abstract: Relapse with drug-resistant disease is the main cause of death in MYCN-amplified neuroblastoma patients. MYCN-amplified neuroblastoma cells in vitro are characterized by a failure to arrest at the G(1)-S checkpoint after irradiation- or drug-induced DNA damage. We show that several MYCN-amplified cell lines harbor additional chromosomal aberrations targeting p53 and/or pRB pathway components, including CDK4/CCND1/MDM2 amplifications, p16INK4A/p14ARF deletions or TP53 mutations. Cells with these additional aberrations undergo significantly lower levels of cell death after doxorubicin treatment compared with MYCN-amplified cells, with no additional mutations in these pathways. In MYCN-amplified cells CDK4 expression is elevated, increasing the competition between CDK4 and CDK2 for binding p21. This results in insufficient p21 to inhibit CDK2, leading to high CDK4 and CDK2 kinase activity upon doxorubicin treatment. CDK4 inhibition by siRNAs, selective small compounds or p19 (INK4D) overexpression partly restored G(1)-S arrest, delayed S-phase progression and reduced cell viability upon doxorubicin treatment. Our results suggest a specific function of p19 (INK4D) , but not p16 (INK4A) , in sensitizing MYCN-amplified cells with a functional p53 pathway to doxorubicin-induced cell death. In summary, the CDK4/cyclin D-pRB axis is altered in MYCN-amplified cells to evade a G(1)-S arrest after doxorubicin-induced DNA damage. Additional chromosomal aberrations affecting the p53-p21 and CDK4-pRB axes compound the effects of MYCN on the G(1) checkpoint and reduce sensitivity to cell death after doxorubicin treatment. CDK4 inhibition partly restores G(1)-S arrest and sensitizes cells to doxorubicin-mediated cell death in MYCN-amplified cells with an intact p53 pathway.
    Type of Publication: Journal article published
    PubMed ID: 23462184
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  • 4
    Keywords: APOPTOSIS ; PATHWAY ; GENES ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; MICE LACKING ; high-throughput analysis ; ISLAND METHYLATOR PHENOTYPE ; D-DEPENDENT KINASES ; INK4 FAMILY
    Abstract: Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d expression was associated with poor event-free and overall survival and neuroblastoma risk factors including amplified MYCN in a set of 478 primary neuroblastomas. High MYCN expression repressed p19-INK4d mRNA and protein levels in different neuroblastoma cell models with conditional MYCN expression. MassARRAY and 450K methylation analyses of 105 primary neuroblastomas uncovered a differentially methylated region within p19-INK4d. Hypermethylation of this region was associated with reduced p19-INK4d expression. In accordance, p19-INK4d expression was activated upon treatment with the demethylating agent, 2'-deoxy-5-azacytidine, in neuroblastoma cell lines. Ectopic p19-INK4d expression decreased viability, clonogenicity and the capacity for anchorage-independent growth of neuroblastoma cells, and shifted the cell cycle towards the G1/0 phase. p19-INK4d also induced neurite-like processes and markers of neuronal differentiation. Moreover, neuroblastoma cell differentiation, induced by all-trans retinoic acid or NGF-NTRK1-signaling, activated p19-/NK4dexpression. Our findings pinpoint p19-INK4d as a neuroblastoma suppressor and provide evidence for MYCN-mediated repression and for epigenetic silencing of p19-INK4d by DNA hypermethylation in high-risk neuroblastomas.
    Type of Publication: Journal article published
    PubMed ID: 25104850
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  • 5
    Keywords: GENE ; neuroblastoma ; ENHANCERS ; LANDSCAPE ; TERT REARRANGEMENTS
    Abstract: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
    Type of Publication: Journal article published
    PubMed ID: 26466568
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  • 6
    Abstract: Signaling pathways control cell fate decisions that ultimately determine the behavior of cancer cells. Therefore, the dynamics of pathway activity may contain prognostically relevant information different from that contained in the static nature of other types of biomarkers. To investigate this hypothesis, we characterized the network that regulated stress signaling by the c-Jun N-terminal kinase (JNK) pathway in neuroblastoma cells. We generated an experimentally calibrated and validated computational model of this network and used the model to extract prognostic information from neuroblastoma patient-specific simulations of JNK activation. Switch-like JNK activation mediates cell death by apoptosis. An inability to initiate switch-like JNK activation in the simulations was significantly associated with poor overall survival for patients with neuroblastoma with or without MYCN amplification, indicating that patient-specific simulations of JNK activation could stratify patients. Furthermore, our analysis demonstrated that extracting information about a signaling pathway to develop a prognostically useful model requires understanding of not only components and disease-associated changes in the abundance or activity of the components but also how those changes affect pathway dynamics.
    Type of Publication: Journal article published
    PubMed ID: 26696630
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  • 7
  • 8
    Abstract: MYCN and HDAC2 jointly repress the transcription of tumor suppressive miR-183 in neuroblastoma. Enforced miR-183 expression induces neuroblastoma cell death and inhibits xenograft growth in mice. Here we aimed to focus more closely on the miR-183 signaling network using a label-free mass spectrometric approach. Analysis of neuroblastoma cells transfected with either control or miR-183 expression vectors identified 85 differentially expressed proteins. All six members of the minichromosome maintenance (MCM) complex, which is indispensable for initiation and elongation during DNA replication and transcriptionally activated by MYCN in neuroblastoma, emerged to be down-regulated by miR-183. Subsequent annotation category enrichment analysis revealed a approximately 14-fold enrichment in the "MCM" protein module category, which highlighted this complex as a critical node in the miR-183 signaling network. Down-regulation was confirmed by Western blotting. MCMs 2-5 were predicted by in silico methods as direct miR-183 targets. Dual-luciferase reporter gene assays with 3'-UTR constructs of the randomly selected MCMs 3 and 5 experimentally confirmed them as direct targets of miR-183. Our results reveal the MCM complex to be a critical and directly regulated node within the miR-183 signaling network in MYCN-amplified neuroblastoma cells.
    Type of Publication: Journal article published
    PubMed ID: 27239679
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  • 9
    Abstract: The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 5523-37. (c)2016 AACR.
    Type of Publication: Journal article published
    PubMed ID: 27635046
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  • 10
    Keywords: LINES ; FREQUENCY ; INDUCED APOPTOSIS ; GENE-MUTATIONS ; WILD-TYPE P53 ; NUCLEAR ; CYTOPLASMIC SEQUESTRATION ; SENSITIZES NEUROBLASTOMA ; ARF TUMOR-SUPPRESSOR ; P53/MDM2/P14(ARF) PATHWAY
    Abstract: Suppression of p53 activity is essential for proliferation and survival of tumor cells. A direct p53-activating compound, nutlin-3, was used in this study, together with p53 mutation analysis, to characterize p53 pathway defects in a set of 34 human neuroblastoma cell lines. We identified 9 cell lines (26%) with a p53 loss-of-function mutation, including 6 missense mutations, 1 nonsense mutation, 1 in-frame deletion, and 1 homozygous deletion of the 30 end of the p53 gene. Sensitivity to nutlin-3 was highly predictive of absence of p53 mutation. Signaling pathways downstream of p53 were functionally intact in 23 of 25 cell lines with wild-type p53. Knockdown and overexpression experiments revealed a potentiating effect of p14(ARF) expression on the response of neuroblastoma cells to nutlin-3. Our findings shed light on the spectrum of p53 pathway lesions in neuroblastoma cells, indicate that defects in effector molecules downstream of p53 are remarkably rare in neuroblastoma, and identify p14(ARF) as a determinant of the outcome of the response to MDM2 inhibition. These insights may prove useful for the clinical translation of evolving strategies aimed at p53 reactivation and for the development of new therapeutic approaches.
    Type of Publication: Journal article published
    PubMed ID: 21460101
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