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  • 1
    Publication Date: 2018-12-07
    Description: Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance–negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
    Keywords: Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Keywords: CANCER ; EXPRESSION ; CELL-PROLIFERATION ; GENES ; PROTEIN ; IDENTIFICATION ; REVEALS ; MicroRNAs ; RELATIVE QUANTIFICATION ; FEEDBACK LOOP
    Abstract: LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3'UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefore establishing an MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promoter, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underline the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process.
    Type of Publication: Journal article published
    PubMed ID: 26123663
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  • 3
    Keywords: RECEPTOR ; CANCER ; GENES ; ASSOCIATION ; PHENOTYPE ; HETEROGENEITY ; N-MYC ; SIGNATURES ; ALK ; DNA METHYLATION DATA
    Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 26121086
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  • 4
    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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  • 5
    Abstract: Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses. Using luciferase reporter assays and chromatin immunoprecipitation we mapped a functional binding site for Myc, a proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter. Pharmacological inhibition or siRNA/shRNA-mediated knock-down of c-Myc or N-Myc significantly decreased B7-H6 expression on a variety of tumor cells including melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines from different origin and primary tumor tissues of hepatocellular carcinoma (HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc in tumor cells impaired NKp30-mediated degranulation of NK cells was observed. Thus, our data imply that Myc driven tumors could be targets for cancer immunotherapy exploiting the NKp30/B7-H6 axis.
    Type of Publication: Journal article published
    PubMed ID: 27622013
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  • 6
    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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  • 7
    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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