title: Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes.
abstract: Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed 192 ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Johann
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Serap
authors.initials: S
authors.lastname: Erkek
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, 48149 Münster, Germany.
authors.forename: Kornelius
authors.initials: K
authors.lastname: Kerl
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Buchhalter
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
authors.forename: David T W
authors.initials: DTW
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Hermann
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Maia
authors.initials: M
authors.lastname: Segura Wang
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Department of Neuropathology, Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Rhyzova
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gröbner
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brabetz
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Institute for Human Genetics, 24105 Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bens
authors.affiliation: Division of Translational Oncology, Nationales Centrum für Tumorerkrankungen NCT, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kratochwil
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wittmann
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Sieber
authors.affiliation: Division of Translational Oncology, Nationales Centrum für Tumorerkrankungen NCT, 69120 Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Geörg
authors.affiliation: Genomics and Proteomics Core Facility, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Beck
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Oyen
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: Volckmann
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 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 Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.affiliation: Department of General Pediatrics, Hematology and Oncology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.affiliation: Department of Neuro-Oncology, Children's Research Center, University Children's Hospital, 8032 Zürich, Switzerland.
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.affiliation: Department of Neuro-Oncology, Children's Research Center, University Children's Hospital, 8032 Zürich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Grotzer
authors.affiliation: Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, 15006 Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Sumerauer
authors.affiliation: Deptartment of Pathology and Molecular Medicine, Charles University, 2nd Medical Faculty, University Hospital Motol, 15006 Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Zamecnik
authors.affiliation: Department of Hematology and Oncology, Children's Hospital, Hospital San Joan de Deu, 08950 Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University Health Center Research Institute, Montreal, QC H3A 1A4, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON M5G0A4, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON M5G0A4, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Neuropathology, Academic Medical Center, 20246 Amsterdam, the Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Bertoni
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.affiliation: Department of Neuropathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Center of Neuropathology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Institute for Human Genetics, 24105 Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Swabian Childrens' Cancer Center, Children's Hospital Augsburg, 86156 Augsburg, Germany; EU-RHAB registry Center, 86156 Augsburg, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Frühwald
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.affiliation: Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany. Electronic address: m.kool@dkfz.de.
authors.forename: Marcel
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authors.lastname: Kool
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D018335:Rhabdoid Tumor / Q000235:genetics*; D000071796:SMARCB1 Protein; D013724:Teratoma / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors