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Cell. 2016 Feb 25;164(5):1060-1072. doi: 10.1016/j.cell.2016.01.015.

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

Sturm D#1,2, Orr BA#3, Toprak UH#4, Hovestadt V#5, Jones DTW1, Capper D6,7, Sill M8, Buchhalter I4, Northcott PA1, Leis I6, Ryzhova M9, Koelsche C6,7, Pfaff E1,2, Allen SJ3, Balasubramanian G10, Worst BC1,2, Pajtler KW1, Brabetz S1, Johann PD1,2, Sahm F6,7, Reimand J11,12, Mackay A13, Carvalho DM13, Remke M14, Phillips JJ15,16,17, Perry A15,16,17, Cowdrey C15, Drissi R18, Fouladi M18, Giangaspero F19,20, Łastowska M21, Grajkowska W21, Scheurlen W22, Pietsch T23, Hagel C24, Gojo J25,26, Lötsch D26, Berger W26, Slavc I25, Haberler C27, Jouvet A28, Holm S29, Hofer S30, Prinz M31, Keohane C32, Fried I33, Mawrin C34, Scheie D35, Mobley BC36, Schniederjan MJ37, Santi M38, Buccoliero AM39, Dahiya S40, Kramm CM41, von Bueren AO41, von Hoff K42, Rutkowski S42, Herold-Mende C43, Frühwald MC44, Milde T2,45, Hasselblatt M46, Wesseling P47,48, Rößler J49, Schüller U50, Ebinger M51, Schittenhelm J52, Frank S53, Grobholz R54, Vajtai I55, Hans V56, Schneppenheim R42, Zitterbart K57, Collins VP58, Aronica E59, Varlet P60, Puget S61, Dufour C62, Grill J62, Figarella-Branger D63, Wolter M64, Schuhmann MU65, Shalaby T66, Grotzer M66, van Meter T67, Monoranu CM68, Felsberg J64, Reifenberger G64, Snuderl M69, Forrester LA70, Koster J71, Versteeg R71, Volckmann R71, van Sluis P71, Wolf S72, Mikkelsen T73, Gajjar A74, Aldape K75, Moore AS76, Taylor MD14, Jones C13, Jabado N77, Karajannis MA78, Eils R4,79,80, Schlesner M4, Lichter P5,80, von Deimling A6,7, Pfister SM1,2, Ellison DW3, Korshunov A6,7, Kool M1.

Author information

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.
#
Contributed equally

Abstract

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.

PMID:
26919435
PMCID:
PMC5139621
[Available on 2017-02-25]
DOI:
10.1016/j.cell.2016.01.015
[Indexed for MEDLINE]
Free PMC Article

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