. 2016 Mar 14;29(3):379-393.

doi: 10.1016/j.ccell.2016.02.001. Epub 2016 Feb 25.

Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

Pascal D Johann¹, Serap Erkek², Marc Zapatka³, Kornelius Kerl⁴, Ivo Buchhalter⁵, Volker Hovestadt³, David T W Jones⁶, Dominik Sturm¹, Carl Hermann⁵, Maia Segura Wang⁷, Andrey Korshunov⁸, Marina Rhyzova⁹, Susanne Gröbner¹⁰, Sebastian Brabetz¹⁰, Lukas Chavez¹⁰, Susanne Bens¹¹, Stefan Gröschel¹², Fabian Kratochwil⁶, Andrea Wittmann⁶, Laura Sieber⁶, Christina Geörg¹², Stefan Wolf¹³, Katja Beck³, Florian Oyen¹⁴, David Capper⁸, Peter van Sluis¹⁵, Richard Volckmann¹⁵, Jan Koster¹⁵, Rogier Versteeg¹⁵, Andreas von Deimling⁸, Till Milde¹⁶, Olaf Witt¹⁶, Andreas E Kulozik¹⁷, Martin Ebinger¹⁸, Tarek Shalaby¹⁹, Michael Grotzer¹⁹, David Sumerauer²⁰, Josef Zamecnik²¹, Jaume Mora²², Nada Jabado²³, Michael D Taylor²⁴, Annie Huang²⁴, Eleonora Aronica²⁵, Anna Bertoni²⁶, Bernhard Radlwimmer²⁶, Torsten Pietsch²⁷, Ulrich Schüller²⁸, Reinhard Schneppenheim¹⁴, Paul A Northcott⁶, Jan O Korbel⁷, Reiner Siebert¹¹, Michael C Frühwald²⁹, Peter Lichter³⁰, Roland Eils³¹, Amar Gajjar³², Martin Hasselblatt³³, Stefan M Pfister¹, Marcel Kool³⁴

Affiliations

¹ 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.
² 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.
³ German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
⁴ Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, 48149 Münster, Germany.
⁵ Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany.
⁶ 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.
⁷ European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
⁸ Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, 69120 Heidelberg, Germany.
⁹ Department of Neuropathology, Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
¹⁰ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
¹¹ Institute for Human Genetics, 24105 Kiel, Germany.
¹² Division of Translational Oncology, Nationales Centrum für Tumorerkrankungen NCT, 69120 Heidelberg, Germany.
¹³ Genomics and Proteomics Core Facility, German Cancer Research Center, 69120 Heidelberg, Germany.
¹⁴ Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹⁵ Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
¹⁶ 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.
¹⁷ Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
¹⁸ Department of General Pediatrics, Hematology and Oncology, University of Tübingen, 72076 Tübingen, Germany.
¹⁹ Department of Neuro-Oncology, Children's Research Center, University Children's Hospital, 8032 Zürich, Switzerland.
²⁰ Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, 15006 Prague, Czech Republic.
²¹ Deptartment of Pathology and Molecular Medicine, Charles University, 2nd Medical Faculty, University Hospital Motol, 15006 Prague, Czech Republic.
²² Department of Hematology and Oncology, Children's Hospital, Hospital San Joan de Deu, 08950 Barcelona, Spain.
²³ Departments of Pediatrics and Human Genetics, McGill University Health Center Research Institute, Montreal, QC H3A 1A4, Canada.
²⁴ Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON M5G0A4, Canada.
²⁵ Department of Neuropathology, Academic Medical Center, 20246 Amsterdam, the Netherlands.
²⁶ Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
²⁷ Department of Neuropathology, University of Bonn, 53127 Bonn, Germany.
²⁸ Center of Neuropathology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
²⁹ Swabian Childrens' Cancer Center, Children's Hospital Augsburg, 86156 Augsburg, Germany; EU-RHAB registry Center, 86156 Augsburg, Germany.
³⁰ 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.
³¹ Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
³² St Jude Children's Research Hospital, Memphis, TN 38105, USA.
³³ Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
³⁴ 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.

PMID: 26923874
DOI: 10.1016/j.ccell.2016.02.001

Free article

Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

Pascal D Johann et al. Cancer Cell. 2016.

Free article

. 2016 Mar 14;29(3):379-393.

doi: 10.1016/j.ccell.2016.02.001. Epub 2016 Feb 25.

Authors

Affiliations

¹ 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.
² 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.
³ German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
⁴ Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, 48149 Münster, Germany.
⁵ Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany.
⁶ 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.
⁷ European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
⁸ Department of Neuropathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center, 69120 Heidelberg, Germany.
⁹ Department of Neuropathology, Burdenko Neurosurgical Institute, 125047 Moscow, Russia.
¹⁰ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
¹¹ Institute for Human Genetics, 24105 Kiel, Germany.
¹² Division of Translational Oncology, Nationales Centrum für Tumorerkrankungen NCT, 69120 Heidelberg, Germany.
¹³ Genomics and Proteomics Core Facility, German Cancer Research Center, 69120 Heidelberg, Germany.
¹⁴ Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹⁵ Department of Oncogenomics, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
¹⁶ 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.
¹⁷ Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
¹⁸ Department of General Pediatrics, Hematology and Oncology, University of Tübingen, 72076 Tübingen, Germany.
¹⁹ Department of Neuro-Oncology, Children's Research Center, University Children's Hospital, 8032 Zürich, Switzerland.
²⁰ Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, 15006 Prague, Czech Republic.
²¹ Deptartment of Pathology and Molecular Medicine, Charles University, 2nd Medical Faculty, University Hospital Motol, 15006 Prague, Czech Republic.
²² Department of Hematology and Oncology, Children's Hospital, Hospital San Joan de Deu, 08950 Barcelona, Spain.
²³ Departments of Pediatrics and Human Genetics, McGill University Health Center Research Institute, Montreal, QC H3A 1A4, Canada.
²⁴ Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON M5G0A4, Canada.
²⁵ Department of Neuropathology, Academic Medical Center, 20246 Amsterdam, the Netherlands.
²⁶ Division of Molecular Genetics, German Cancer Research Center, 69120 Heidelberg, Germany.
²⁷ Department of Neuropathology, University of Bonn, 53127 Bonn, Germany.
²⁸ Center of Neuropathology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
²⁹ Swabian Childrens' Cancer Center, Children's Hospital Augsburg, 86156 Augsburg, Germany; EU-RHAB registry Center, 86156 Augsburg, Germany.
³⁰ 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.
³¹ Division of Theoretical Bioinformatics, German Cancer Research Center, 69120 Heidelberg, Germany; Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, 69120 Heidelberg, Germany.
³² St Jude Children's Research Hospital, Memphis, TN 38105, USA.
³³ Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
³⁴ 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.

PMID: 26923874
DOI: 10.1016/j.ccell.2016.02.001

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.

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A Molecular Take on Malignant Rhabdoid Tumors.
Tang M, Verhaak RG. Tang M, et al. Trends Cancer. 2016 May;2(5):217-218. doi: 10.1016/j.trecan.2016.04.003. Trends Cancer. 2016. PMID: 27672680 Free PMC article.

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Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

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Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes

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