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  • 1
    Publication Date: 2012-07-27
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662966/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, David T W -- Jager, Natalie -- Kool, Marcel -- Zichner, Thomas -- Hutter, Barbara -- Sultan, Marc -- Cho, Yoon-Jae -- Pugh, Trevor J -- Hovestadt, Volker -- Stutz, Adrian M -- Rausch, Tobias -- Warnatz, Hans-Jorg -- Ryzhova, Marina -- Bender, Sebastian -- Sturm, Dominik -- Pleier, Sabrina -- Cin, Huriye -- Pfaff, Elke -- Sieber, Laura -- Wittmann, Andrea -- Remke, Marc -- Witt, Hendrik -- Hutter, Sonja -- Tzaridis, Theophilos -- Weischenfeldt, Joachim -- Raeder, Benjamin -- Avci, Meryem -- Amstislavskiy, Vyacheslav -- Zapatka, Marc -- Weber, Ursula D -- Wang, Qi -- Lasitschka, Barbel -- Bartholomae, Cynthia C -- Schmidt, Manfred -- von Kalle, Christof -- Ast, Volker -- Lawerenz, Chris -- Eils, Jurgen -- Kabbe, Rolf -- Benes, Vladimir -- van Sluis, Peter -- Koster, Jan -- Volckmann, Richard -- Shih, David -- Betts, Matthew J -- Russell, Robert B -- Coco, Simona -- Tonini, Gian Paolo -- Schuller, Ulrich -- Hans, Volkmar -- Graf, Norbert -- Kim, Yoo-Jin -- Monoranu, Camelia -- Roggendorf, Wolfgang -- Unterberg, Andreas -- Herold-Mende, Christel -- Milde, Till -- Kulozik, Andreas E -- von Deimling, Andreas -- Witt, Olaf -- Maass, Eberhard -- Rossler, Jochen -- Ebinger, Martin -- Schuhmann, Martin U -- Fruhwald, Michael C -- Hasselblatt, Martin -- Jabado, Nada -- Rutkowski, Stefan -- von Bueren, Andre O -- Williamson, Dan -- Clifford, Steven C -- McCabe, Martin G -- Collins, V Peter -- Wolf, Stephan -- Wiemann, Stefan -- Lehrach, Hans -- Brors, Benedikt -- Scheurlen, Wolfram -- Felsberg, Jorg -- Reifenberger, Guido -- Northcott, Paul A -- Taylor, Michael D -- Meyerson, Matthew -- Pomeroy, Scott L -- Yaspo, Marie-Laure -- Korbel, Jan O -- Korshunov, Andrey -- Eils, Roland -- Pfister, Stefan M -- Lichter, Peter -- P30 HD018655/HD/NICHD NIH HHS/ -- R01 CA109467/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):100-5. doi: 10.1038/nature11284.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22832583" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics ; Amino Acid Sequence ; Cell Transformation, Neoplastic ; Cerebellar Neoplasms/classification/diagnosis/*genetics/pathology ; Child ; Chromatin/metabolism ; Chromosomes, Human/genetics ; DEAD-box RNA Helicases/genetics ; DNA Helicases/genetics ; DNA-Binding Proteins/genetics ; Genome, Human/*genetics ; Genomics ; Hedgehog Proteins/metabolism ; High-Throughput Nucleotide Sequencing ; Histone Demethylases/genetics ; Humans ; Medulloblastoma/classification/diagnosis/*genetics/pathology ; Methylation ; Mutation/genetics ; Mutation Rate ; Neoplasm Proteins/genetics ; Nuclear Proteins/genetics ; Oncogene Proteins, Fusion/genetics ; Phosphoprotein Phosphatases/genetics ; Polyploidy ; Receptors, Cell Surface/genetics ; Sequence Analysis, RNA ; Signal Transduction ; T-Box Domain Proteins/genetics ; Transcription Factors/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-05-23
    Description: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hovestadt, Volker -- Jones, David T W -- Picelli, Simone -- Wang, Wei -- Kool, Marcel -- Northcott, Paul A -- Sultan, Marc -- Stachurski, Katharina -- Ryzhova, Marina -- Warnatz, Hans-Jorg -- Ralser, Meryem -- Brun, Sonja -- Bunt, Jens -- Jager, Natalie -- Kleinheinz, Kortine -- Erkek, Serap -- Weber, Ursula D -- Bartholomae, Cynthia C -- von Kalle, Christof -- Lawerenz, Chris -- Eils, Jurgen -- Koster, Jan -- Versteeg, Rogier -- Milde, Till -- Witt, Olaf -- Schmidt, Sabine -- Wolf, Stephan -- Pietsch, Torsten -- Rutkowski, Stefan -- Scheurlen, Wolfram -- Taylor, Michael D -- Brors, Benedikt -- Felsberg, Jorg -- Reifenberger, Guido -- Borkhardt, Arndt -- Lehrach, Hans -- Wechsler-Reya, Robert J -- Eils, Roland -- Yaspo, Marie-Laure -- Landgraf, Pablo -- Korshunov, Andrey -- Zapatka, Marc -- Radlwimmer, Bernhard -- Pfister, Stefan M -- Lichter, Peter -- England -- Nature. 2014 Jun 26;510(7506):537-41. doi: 10.1038/nature13268. Epub 2014 May 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany. ; Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia. ; Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)-Designated Cancer Center, Sanford-Burnham Medical Research Institute, 2880 Torrey Pines Scenic Drive, La Jolla, California 92037, USA. ; 1] Queensland Brain Institute, University of Queensland, QBI Building, St Lucia, Queensland 4072, Australia [2] Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany. ; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany. ; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. ; 1] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany [2] Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, Bonn 53105, Germany. ; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. ; Cnopf'sche Kinderklinik, Nurnberg Children's Hospital, St.-Johannis-Muhlgasse 19, Nurnberg 90419, Germany. ; 1] Program in Developmental and Stem Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [2] Division of Neurosurgery, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Neuropathology, Heinrich Heine University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany [2] German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Institute of Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Heidelberg 69120, Germany [3] Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg 69120, Germany [4] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany [2] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 220-221, Heidelberg, 69120 Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847876" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line, Tumor ; Chromatin/genetics/metabolism ; Chromatin Immunoprecipitation ; DNA Methylation/*genetics ; Female ; *Gene Expression Regulation, Neoplastic ; *Gene Silencing ; Genome/genetics ; Histones/metabolism ; Humans ; Medulloblastoma/*genetics/pathology ; Mice ; Promoter Regions, Genetic/genetics ; RNA-Binding Proteins/genetics ; Sequence Analysis, DNA/*methods ; Transcription Factors/metabolism ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-01-28
    Description: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Charles Y -- Erkek, Serap -- Tong, Yiai -- Yin, Linlin -- Federation, Alexander J -- Zapatka, Marc -- Haldipur, Parthiv -- Kawauchi, Daisuke -- Risch, Thomas -- Warnatz, Hans-Jorg -- Worst, Barbara C -- Ju, Bensheng -- Orr, Brent A -- Zeid, Rhamy -- Polaski, Donald R -- Segura-Wang, Maia -- Waszak, Sebastian M -- Jones, David T W -- Kool, Marcel -- Hovestadt, Volker -- Buchhalter, Ivo -- Sieber, Laura -- Johann, Pascal -- Chavez, Lukas -- Groschel, Stefan -- Ryzhova, Marina -- Korshunov, Andrey -- Chen, Wenbiao -- Chizhikov, Victor V -- Millen, Kathleen J -- Amstislavskiy, Vyacheslav -- Lehrach, Hans -- Yaspo, Marie-Laure -- Eils, Roland -- Lichter, Peter -- Korbel, Jan O -- Pfister, Stefan M -- Bradner, James E -- Northcott, Paul A -- England -- Nature. 2016 Feb 4;530(7588):57-62. doi: 10.1038/nature16546. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA. ; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Bone Marrow Transplantation &Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Oncology, NCT Heidelberg, 69120 Heidelberg, Germany. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 125047 Moscow, Russia. ; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, 69120 Heidelberg, Germany. ; Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA. ; Department of Pediatrics, Genetics Division, University of Washington, Seattle, Washington 98195, USA. ; Institute of Pharmacy and Molecular Biotechnology and BioQuant, University of Heidelberg, 69117 Heidelberg, Germany. ; Department of Pediatrics, University of Heidelberg, 69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814967" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cerebellar Neoplasms/classification/*genetics/*pathology ; Enhancer Elements, Genetic/*genetics ; Female ; Gene Expression Regulation, Neoplastic/*genetics ; Gene Regulatory Networks/genetics ; Genes, Neoplasm/genetics ; Genes, Reporter/genetics ; Humans ; Male ; Medulloblastoma/*classification/genetics/*pathology ; Mice ; Reproducibility of Results ; Transcription Factors/*metabolism ; Zebrafish/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-07-22
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Northcott, Paul A -- Lee, Catherine -- Zichner, Thomas -- Stutz, Adrian M -- Erkek, Serap -- Kawauchi, Daisuke -- Shih, David J H -- Hovestadt, Volker -- Zapatka, Marc -- Sturm, Dominik -- Jones, David T W -- Kool, Marcel -- Remke, Marc -- Cavalli, Florence M G -- Zuyderduyn, Scott -- Bader, Gary D -- VandenBerg, Scott -- Esparza, Lourdes Adriana -- Ryzhova, Marina -- Wang, Wei -- Wittmann, Andrea -- Stark, Sebastian -- Sieber, Laura -- Seker-Cin, Huriye -- Linke, Linda -- Kratochwil, Fabian -- Jager, Natalie -- Buchhalter, Ivo -- Imbusch, Charles D -- Zipprich, Gideon -- Raeder, Benjamin -- Schmidt, Sabine -- Diessl, Nicolle -- Wolf, Stephan -- Wiemann, Stefan -- Brors, Benedikt -- Lawerenz, Chris -- Eils, Jurgen -- Warnatz, Hans-Jorg -- Risch, Thomas -- Yaspo, Marie-Laure -- Weber, Ursula D -- Bartholomae, Cynthia C -- von Kalle, Christof -- Turanyi, Eszter -- Hauser, Peter -- Sanden, Emma -- Darabi, Anna -- Siesjo, Peter -- Sterba, Jaroslav -- Zitterbart, Karel -- Sumerauer, David -- van Sluis, Peter -- Versteeg, Rogier -- Volckmann, Richard -- Koster, Jan -- Schuhmann, Martin U -- Ebinger, Martin -- Grimes, H Leighton -- Robinson, Giles W -- Gajjar, Amar -- Mynarek, Martin -- von Hoff, Katja -- Rutkowski, Stefan -- Pietsch, Torsten -- Scheurlen, Wolfram -- Felsberg, Jorg -- Reifenberger, Guido -- Kulozik, Andreas E -- von Deimling, Andreas -- Witt, Olaf -- Eils, Roland -- Gilbertson, Richard J -- Korshunov, Andrey -- Taylor, Michael D -- Lichter, Peter -- Korbel, Jan O -- Wechsler-Reya, Robert J -- Pfister, Stefan M -- 5P30CA030199/CA/NCI NIH HHS/ -- P01 CA096832/CA/NCI NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P41GM103504/GM/NIGMS NIH HHS/ -- R01 CA159859/CA/NCI NIH HHS/ -- England -- Nature. 2014 Jul 24;511(7510):428-34. doi: 10.1038/nature13379. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; 1] Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA [2] Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [3]. ; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2]. ; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada. ; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany. ; Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany. ; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary. ; 2nd Department of Pediatrics, Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary. ; 1] Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden [2] Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden. ; Department of Pediatric Oncology, Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic. ; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Uvalu 84, Prague 150 06, Czech Republic. ; Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands. ; Department of Neurosurgery, Tubingen University Hospital, Hoppe-Seyler Strasse 3, Tubingen 72076, Germany. ; Division of Immunobiology, Program in Cancer Pathology of the Divisions of Experimental Hematology and Pathology, Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA. ; 1] Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2] Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. ; Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany. ; Cnopf'sche Kinderklinik, Nurnberg Children's Hospital, St-Johannis-Muhlgasse 19, Nurnberg 90419, Germany. ; Department of Neuropathology, Heinrich-Heine-University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany. ; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. ; Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany. ; 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [2] Division of Neurosurgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2] EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043047" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Child ; Chromosomes, Human, Pair 9/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Enhancer Elements, Genetic/*genetics ; Genomic Structural Variation/*genetics ; Humans ; Medulloblastoma/classification/*genetics/pathology ; Mice ; Oncogenes/*genetics ; Proto-Oncogene Proteins/*genetics/metabolism ; Repressor Proteins/*genetics/metabolism ; Transcription Factors/*genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Keywords: RECEPTOR ; MECHANISM ; DELETION ; PROGRESSION ; MEN ; MYELOID-LEUKEMIA ; REARRANGEMENTS ; GENE FUSIONS ; SEQUENCING DATA ; PSA RECURRENCE
    Abstract: Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of 〉 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA.
    Type of Publication: Journal article published
    PubMed ID: 23410972
    Signatur Availability
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