title: Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups.
abstract: Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, 45147 Essen, Germany.
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Pajtler
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sill
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kratochwil
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Khalida
authors.initials: K
authors.lastname: Wani
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Tatevossian
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Chandanamali
authors.initials: C
authors.lastname: Punchihewa
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Pascal
authors.initials: P
authors.lastname: Johann
authors.affiliation: The Donnelly Center, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Hans-Jörg
authors.initials: HJ
authors.lastname: Warnatz
authors.affiliation: Department of Neuropathology, NN Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Mack
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Leonille
authors.initials: L
authors.lastname: Schweizer
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Sieber
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wittmann
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Volckmann
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105AZ Amsterdam, the Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fults
authors.affiliation: Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, 49202 Petah Tikva, Israel.
authors.forename: Helen
authors.initials: H
authors.lastname: Toledano
authors.affiliation: Department of Molecular Oncology, Schneider Children's Medical Center of Israel, Tel Aviv University, 49202 Tel Aviv, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Hoffman
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Foreman
authors.affiliation: Department of Pathology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Hewer
authors.affiliation: Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno and Masaryk University, 61300 Brno, Czech Republic; Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 65653 Brno, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Zitterbart
authors.affiliation: Division of Cancer Medicine, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Gilbert
authors.affiliation: Division of Cancer Medicine, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Family Health, University of Texas Health Science Center-SON, Houston, TX 77030, USA.
authors.forename: Terri S
authors.initials: TS
authors.lastname: Armstrong
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Departments of Pediatrics and Neurology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Allen
authors.affiliation: Division of Pediatric Hematology and Oncology, Departments of Pediatrics and Otolaryngology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Karajannis
authors.affiliation: Department of Pathology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.affiliation: Institute for Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Martin
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authors.lastname: Hasselblatt
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Hospital, 69120 Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University Hospital, 69120 Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1TN, UK.
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: von Hoff
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.affiliation: Department of Neuropathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: The Donnelly Center, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Bader
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Yaspo
authors.affiliation: Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gilbertson
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.affiliation: Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: m.kool@dkfz.de.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: s.pfister@dkfz.de.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000145:classification / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004806:Ependymoma / Q000145:classification / Q000235:genetics / Q000473:pathology*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D050939:Gene Fusion; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091102:YAP-Signaling Proteins; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human