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      New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

      research-article
      1 , 2 , 3 , 4 , 5 , 1 , 6 , 7 , 8 , 4 , 1 , 6 , 9 , 6 , 7 , 1 , 2 , 3 , 10 , 1 , 2 , 1 , 1 , 1 , 2 , 6 , 7 , 11 , 12 , 13 , 13 , 14 , 15 , 16 , 17 , 15 , 16 , 17 , 15 , 18 , 18 , 19 , 20 , 21 , 21 , 22 , 23 , 24 , 25 , 26 , 26 , 26 , 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 41 , 42 , 42 , 43 , 44 , 2 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 42 , 57 , 58 , 59 , 60 , 61 , 62 , 62 , 63 , 64 , 65 , 66 , 66 , 67 , 68 , 64 , 64 , 69 , 70 , 71 , 71 , 71 , 71 , 72 , 73 , 74 , 75 , 76 , 14 , 13 , 77 , 78 , 4 , 79 , 80 , 4 , 5 , 80 , 6 , 7 , 1 , 2 , 3 , 6 , 7 , 1
      Cell
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          SUMMARY

          Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated “CNS neuroblastoma with FOXR2 activation (CNS NB- FOXR2)”, “CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT- CIC)”, “CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET- MN1)”, and “CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET- BCOR)”, will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

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          Author and article information

          Journal
          0413066
          2830
          Cell
          Cell
          Cell
          0092-8674
          1097-4172
          24 November 2016
          25 February 2016
          25 February 2017
          : 164
          : 5
          : 1060-1072
          Affiliations
          [1 ] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
          [2 ] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
          [3 ] Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
          [4 ] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
          [5 ] Division of Molecular Genetics, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
          [6 ] Department of Neuropathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
          [7 ] Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg.
          [8 ] Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
          [9 ] NN Burdenko Neurosurgical Institute, Moscow, 125047 Russia.
          [10 ] Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
          [11 ] Ontario Institute for Cancer Research, M5G 0A3, Toronto, ON M5G 1L7, Canada.
          [12 ] Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
          [13 ] Division of Molecular Pathology, The Institute of Cancer Research, SW7 3RP, London, United Kingdom.
          [14 ] Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON M4N 1X8, Canada.
          [15 ] Brain Tumor Research Center, University of California, San Francisco, CA 94158-9001, USA.
          [16 ] Neuropathology, Department of Pathology, University of California, San Francisco, CA 94143-0102, USA.
          [17 ] Department of Neurological Surgery, University of California, San Francisco, CA 94143-0112, USA.
          [18 ] Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
          [19 ] Department of Radiological, Oncological and Anatomic-Pathological Sciences, Sapienza University of Rome, 00185 Rome, Italy.
          [20 ] IRCCS Neuromed, 86077 Pozzilli, Molise, Italy.
          [21 ] Department of Pathology, Children's Memorial Health Institute, 04-730 Warsaw, Poland.
          [22 ] Cnopf'sche Kinderklinik, Nürnberg Children's Hospital, 90419 Nürnberg, Germany.
          [23 ] Department of Neuropathology, University of Bonn Medical School, 53105 Bonn, Germany.
          [24 ] Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
          [25 ] Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
          [26 ] Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
          [27 ] Institute of Neurology, Medical University of Vienna, 1097 Vienna, Austria.
          [28 ] Neuro-Oncology and Neuro-Inflammation Team, Inserm U1028, CNRS UMR 5292, University Lyon-1, Neuroscience Center, 69000 Lyon, France, and Centre de Pathologie et de Neuropathologie Est, Hospices Civils de Lyon, 69003 Lyon, France.
          [29 ] Department of Women's and Children's Health (KBH), Karolinska Institutet, SE-171 77 Stockholm, Sweden.
          [30 ] Department of Oncology, Luzerner Kantonsspital, 6000 Luzern 16, Luzern, Switzerland.
          [31 ] Institute of Neuropathology, University of Freiburg, Germany & BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79106 Freiburg, Germany.
          [32 ] Department of Pathology, University College Cork and Cork University Hospital Wilton, Cork, Ireland.
          [33 ] Department of Pediatric Hematology and Oncology, Hadassah Medical Center, Jerusalem, Israel.
          [34 ] Institute of Neuropathology, University Hospital, Otto-von-Guericke University, 39120 Magdeburg, Germany.
          [35 ] Department of Pathology, Copenhagen University Hospital, 2100 København Ø, Denmark.
          [36 ] Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
          [37 ] Department of Pathology and Laboratory Administration, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA.
          [38 ] Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
          [39 ] Pathology Unit, Anna Meyer Children's University Hospital, 50141 Florence, Italy.
          [40 ] Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
          [41 ] Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Göttingen, 37075 Göttingen, Germany.
          [42 ] Department of Pediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
          [43 ] Department of Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany.
          [44 ] Pediatric Hospital, Klinikum Augsburg, 86156 Augsburg, Germany.
          [45 ] Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) Heidelberg, 69120 Heidelberg, Germany.
          [46 ] Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
          [47 ] Department of Pathology, VU University Medical Center Amsterdam, 1008 MB Amsterdam, The Netherlands.
          [48 ] Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, 6525 GA, The Netherlands.
          [49 ] Department of Pediatric Hematology/Oncology, Center of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany.
          [50 ] Department of Neuropathology, Ludwig-Maximilians-University, and German Cancer Consortium (DKTK) partner site Munich, 81377 Munich, Germany.
          [51 ] Department of Hematology and Oncology, Children's University Hospital Tübingen, and German Cancer Consortium (DKTK) partner site Tübingen, 72076 Tübingen, Germany.
          [52 ] Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, and German Cancer Consortium (DKTK) partner site Tübingen, 72076 Tübingen, Germany.
          [53 ] Department of Neuropathology, Institute of Pathology, Basel University Hospital, 4031 Basel, Switzerland.
          [54 ] Department of Pathology, Medical Center Aarau, 5001 Aarau, Switzerland.
          [55 ] Department of Pathology, University Hospital Bern, 3010 Bern, Switzerland.
          [56 ] Department of Neuropathology, Medical Center Bielefeld, 33617 Bielefeld, Germany.
          [57 ] Department of Pediatric Oncology, University Hospital Brno and Masaryk University, Faculty of Medicine, 613 00 Brno, Czech Republic.
          [58 ] Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
          [59 ] Department of Neuropathology, AMC, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands.
          [60 ] Department of Neuropathology, Hôpital Sainte-Anne, 75674, Paris, France.
          [61 ] Pediatric Neurosurgery Department, Necker Enfants Malades Hospital, 75015, Paris, France.
          [62 ] Brain Tumor Program, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, University Paris Sud, 94805, Villejuif, France.
          [63 ] Department of Pathology and Neuropathology, la Timone Hospital, AP-HM and UMR911 CR02, Aix-Marseille University, 13385 Marseille, France.
          [64 ] Department of Neuropathology, Heinrich-Heine-University, and German Cancer Consortium (DKTK) partner site Essen/Düsseldorf, 40225 Düsseldorf, Germany.
          [65 ] Department of Neurosurgery, Section of Pediatric Neurosurgery, University Hospital Tübingen, and German Cancer Consortium (DKTK) partner site Tübingen, 72076 Tübingen, Germany.
          [66 ] Neuro-Oncology Program, Division of Oncology, University Children's Hospital Zurich, 8032 Zürich, Switzerland.
          [67 ] Virginia Commonwealth University, Richmond, VA 23298, USA.
          [68 ] Department of Neuropathology, Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center (CCC) Mainfranken, University and University Hospital, 97080 Würzburg, Germany.
          [69 ] Department of Pathology, Division of Neuropathology, NYU Langone Medical Center, New York, NY 10016, USA.
          [70 ] NYU School of Medicine, New York, NY 10016, USA.
          [71 ] Department of Oncogenomics, AMC, University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands.
          [72 ] Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
          [73 ] Departments of Neurology and Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
          [74 ] Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
          [75 ] Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
          [76 ] The University of Queensland Diamantina Institute, Translational Research Institute; UQ Child Health Research Centre, The University of Queensland; Queensland Children's Medical Research Institute, Children's Health Queensland Hospital and Health Service; Brisbane, Australia.
          [77 ] McGill University and Genome Quebec Innovation Centre, Montreal, QC H3A 1A4, Canada.
          [78 ] Departments of Pediatrics and Otolaryngology, Division of Pediatric Hematology/Oncology, NYU Langone Medical Center and Laura and Isaac Perlmutter Cancer Center, NY 10016, New York, USA.
          [79 ] Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
          [80 ] Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
          Author notes
          [#]

          Co-senior authors

          Correspondence: Marcel Kool ( m.kool@ 123456dkfz.de )
          Article
          PMC5139621 PMC5139621 5139621 nihpa805491
          10.1016/j.cell.2016.01.015
          5139621
          26919435
          c8bb0e6d-cc65-43af-90fa-d1ba90b9ed78
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