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.

Brain Tumor Program Department of Pediatric and Adolescent Oncology Gustave Roussy Cancer Institute University Paris Sud 94805 Villejuif France

Brain Tumor Research Center University of California San Francisco CA 94158 9001 USA

Clinical Cooperation Unit Neuropathology German Cancer Research Center 69120 Heidelberg

Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center Heidelberg 69120 Heidelberg Germany

Cnopf'sche Kinderklinik Nürnberg Children's Hospital 90419 Nürnberg Germany

Department for Bioinformatics and Functional Genomics Institute for Pharmacy and Molecular Biotechnology and BioQuant Heidelberg University Heidelberg Germany

Department of Hematology and Oncology Children's University Hospital Tübingen and German Cancer Consortium partner site Tübingen 72076 Tübingen Germany

Department of Medical Biophysics University of Toronto Toronto ON M5G 1L7 Canada

Department of Medicine 1 Institute of Cancer Research and Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Neuro Oncology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Department of Neurological Surgery University of California San Francisco CA 94143 0112 USA

Department of Neuropathology AMC University of Amsterdam Amsterdam 1105 AZ The Netherlands

Department of Neuropathology Heidelberg University Hospital 69120 Heidelberg Germany

Department of Neuropathology Heinrich Heine University and German Cancer Consortium partner site Essen Düsseldorf 40225 Düsseldorf Germany

Department of Neuropathology Hôpital Sainte Anne 75674 Paris France

Department of Neuropathology Institute of Pathology and Neuropathology University of Tübingen and German Cancer Consortium partner site Tübingen 72076 Tübingen Germany

Department of Neuropathology Institute of Pathology Basel University Hospital 4031 Basel Switzerland

Department of Neuropathology Institute of Pathology University of Würzburg and Comprehensive Cancer Center Mainfranken University and University Hospital 97080 Würzburg Germany

Department of Neuropathology Ludwig Maximilians University and German Cancer Consortium partner site Munich 81377 Munich Germany

Department of Neuropathology Medical Center Bielefeld 33617 Bielefeld Germany

Department of Neuropathology University of Bonn Medical School 53105 Bonn Germany

Department of Neurosurgery Heidelberg University Hospital 69120 Heidelberg Germany

Department of Neurosurgery Section of Pediatric Neurosurgery University Hospital Tübingen and German Cancer Consortium partner site Tübingen 72076 Tübingen Germany

Department of Oncogenomics AMC University of Amsterdam Amsterdam 1105 AZ The Netherlands

Department of Oncology Luzerner Kantonsspital 6000 Luzern 16 Luzern Switzerland

Department of Oncology St Jude Children's Research Hospital Memphis TN 38105 USA

Department of Pathology and Immunology Washington University St Louis MO 63110 USA

Department of Pathology and Laboratory Administration Children's Healthcare of Atlanta Atlanta GA 30322 USA

Department of Pathology and Neuropathology la Timone Hospital AP HM and UMR911 CR02 Aix Marseille University 13385 Marseille France

Department of Pathology Children's Hospital of Philadelphia Philadelphia PA 19104 USA

Department of Pathology Children's Memorial Health Institute 04 730 Warsaw Poland

Department of Pathology Copenhagen University Hospital 2100 København Ø Denmark

Department of Pathology Division of Neuropathology NYU Langone Medical Center New York NY 10016 USA

Department of Pathology Medical Center Aarau 5001 Aarau Switzerland

Department of Pathology Microbiology and Immunology Vanderbilt University Medical Center Nashville TN 37232 USA

Department of Pathology Radboud University Nijmegen Medical Center Nijmegen 6525 GA The Netherlands

Department of Pathology St Jude Children's Research Hospital Memphis TN 38105 3678 USA

Department of Pathology University College Cork and Cork University Hospital Wilton Cork Ireland

Department of Pathology University Hospital Bern 3010 Bern Switzerland

Department of Pathology VU University Medical Center Amsterdam 1008 MB Amsterdam The Netherlands

Department of Pediatric Haematology and Oncology University Medical Center Hamburg Eppendorf 20246 Hamburg Germany

Department of Pediatric Hematology and Oncology Hadassah Medical Center Jerusalem Israel

Department of Pediatric Hematology Oncology Center of Pediatrics and Adolescent Medicine University Medical Center Freiburg 79106 Freiburg Germany

Department of Pediatric Oncology Hematology and Immunology Heidelberg University Hospital 69120 Heidelberg Germany

Department of Pediatric Oncology University Hospital Brno and Masaryk University Faculty of Medicine 613 00 Brno Czech Republic

Department of Pediatrics and Adolescent Medicine Medical University of Vienna 1090 Vienna Austria

Department of Radiological Oncological and Anatomic Pathological Sciences Sapienza University of Rome 00185 Rome Italy

Department of Women's and Children's Health Karolinska Institutet SE 171 77 Stockholm Sweden

Departments of Neurology and Neurosurgery Henry Ford Hospital Detroit MI 48202 USA

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

Division of Applied Bioinformatics German Cancer Research Center 69120 Heidelberg Germany

Division of Biostatistics German Cancer Research Center 69120 Heidelberg Germany

Division of Molecular Genetics German Cancer Research Center 69120 Heidelberg Germany

Division of Molecular Histopathology Department of Pathology University of Cambridge Cambridge CB2 0QQ United Kingdom

Division of Molecular Pathology The Institute of Cancer Research SW7 3RP London United Kingdom

Division of Oncology Cincinnati Children's Hospital Medical Center Cincinnati OH 45229 USA

Division of Pediatric Hematology and Oncology Department of Child and Adolescent Health University Medical Center Göttingen 37075 Göttingen Germany

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Division of Theoretical Bioinformatics German Cancer Research Center 69120 Heidelberg Germany

Genomics and Proteomics Core Facility High Throughput Sequencing Unit German Cancer Research Center 69120 Heidelberg Germany

Heidelberg Center for Personalized Oncology DKFZ HIPO DKFZ Im Neuenheimer Feld 580 69120 Heidelberg Germany

Institute of Neurology Medical University of Vienna 1097 Vienna Austria

Institute of Neuropathology University Hospital Münster 48149 Münster Germany

Institute of Neuropathology University Hospital Otto von Guericke University 39120 Magdeburg Germany

Institute of Neuropathology University Medical Center Hamburg Eppendorf 20246 Hamburg Germany

Institute of Neuropathology University of Freiburg Germany and BIOSS Centre for Biological Signalling Studies University of Freiburg 79106 Freiburg Germany

IRCCS Neuromed 86077 Pozzilli Molise Italy

McGill University and Genome Quebec Innovation Centre Montreal QC H3A 1A4 Canada

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

Neuro Oncology Program Division of Oncology University Children's Hospital Zurich 8032 Zürich Switzerland

Neuropathology Department of Pathology University of California San Francisco CA 94143 0102 USA

NN Burdenko Neurosurgical Institute Moscow 125047 Russia

NYU School of Medicine New York NY 10016 USA

Ontario Institute for Cancer Research M5G 0A3 Toronto ON M5G 1L7 Canada

Pathology Unit Anna Meyer Children's University Hospital 50141 Florence Italy

Pediatric Hospital Klinikum Augsburg 86156 Augsburg Germany

Pediatric Neurosurgery Department Necker Enfants Malades Hospital 75015 Paris France

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

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

Virginia Commonwealth University Richmond VA 23298 USA

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Cell. 2016 Feb 25;164(5):844-6. doi: 10.1016/j.cell.2016.02.030. PubMed

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