Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

S. C. Mack, H. Witt, R. M. Piro, L. Gu, S. Zuyderduyn, A. M. Stütz, X. Wang, M. Gallo, L. Garzia, K. Zayne, X. Zhang, V. Ramaswamy, N. Jäger, D. T. W. Jones, M. Sill, T. J. Pugh, M. Ryzhova, K. M. Wani, D. J. H. Shih, R. Head, M. Remke, S. D. Bailey, T. Zichner, C. C. Faria, M. Barszczyk, S. Stark, H. Seker-Cin, S. Hutter, P. Johann, S. Bender, V. Hovestadt, T. Tzaridis, A. M. Dubuc, P. A. Northcott, J. Peacock, K. C. Bertrand, S. Agnihotri, F. M. G. Cavalli, I. Clarke, K. Nethery-Brokx, C. L. Creasy, S. K. Verma, J. Koster, X. Wu, Y. Yao, T. Milde, P. Sin-Chan, J. Zuccaro, L. Lau, S. Pereira, P. Castelo-Branco, M. Hirst, M. A. Marra, S. S. Roberts, D. Fults, L. Massimi, Y. J. Cho, T. Van Meter, W. Grajkowska, B. Lach, A. E. Kulozik, A. von Deimling, O. Witt, S. W. Scherer, X. Fan, K. M. Muraszko, M. Kool, S. L. Pomeroy, N. Gupta, J. Phillips, A. Huang, U. Tabori, C. Hawkins, D. Malkin, P. N. Kongkham, W. A. Weiss, N. Jabado, J. T. Rutka, E. Bouffet, J. O. Korbel, M. Lupien, K. D. Aldape, G. D. Bader, R. Eils, P. Lichter, P. B. Dirks, S. M. Pfister, A. Korshunov () and M. D. Taylor ()
Additional contact information
S. C. Mack: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
H. Witt: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
R. M. Piro: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
L. Gu: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
S. Zuyderduyn: The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada
A. M. Stütz: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
X. Wang: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
M. Gallo: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
L. Garzia: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
K. Zayne: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
X. Zhang: Norris Cotton Cancer Center, Dartmouth Medical School
V. Ramaswamy: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
N. Jäger: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
D. T. W. Jones: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
M. Sill: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
T. J. Pugh: Harvard Medical School, Children’s Hospital Boston, MIT, Boston, Massachusetts 02115, USA
M. Ryzhova: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
K. M. Wani: The University of Texas MD Anderson Cancer Center
D. J. H. Shih: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
R. Head: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
M. Remke: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
S. D. Bailey: Ontario Cancer Institute, Princess Margaret Cancer Centre–University Health Network, Toronto, Ontario M5G 1L7, Canada
T. Zichner: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
C. C. Faria: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
M. Barszczyk: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
S. Stark: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
H. Seker-Cin: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
S. Hutter: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
P. Johann: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
S. Bender: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
V. Hovestadt: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
T. Tzaridis: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
A. M. Dubuc: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
P. A. Northcott: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
J. Peacock: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
K. C. Bertrand: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
S. Agnihotri: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
F. M. G. Cavalli: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
I. Clarke: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
K. Nethery-Brokx: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
C. L. Creasy: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville
S. K. Verma: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville
J. Koster: Academic Medical Center, Amsterdam 1105, The Netherlands
X. Wu: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
Y. Yao: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
T. Milde: Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany
P. Sin-Chan: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
J. Zuccaro: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
L. Lau: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
S. Pereira: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
P. Castelo-Branco: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
M. Hirst: Centre for High-Throughput Biology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada
M. A. Marra: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
S. S. Roberts: Uniformed Services University
D. Fults: University of Utah School of Medicine
L. Massimi: Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy
Y. J. Cho: Stanford University School of Medicine
T. Van Meter: Virginia Commonwealth
W. Grajkowska: University of Warsaw, Children’s Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland
B. Lach: McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada
A. E. Kulozik: Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany
A. von Deimling: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
O. Witt: Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany
S. W. Scherer: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
X. Fan: University of Michigan Cell and Developmental Biology
K. M. Muraszko: University of Michigan Medical School
M. Kool: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
S. L. Pomeroy: Harvard Medical School, Children’s Hospital Boston, MIT, Boston, Massachusetts 02115, USA
N. Gupta: University of California San Francisco
J. Phillips: Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA
A. Huang: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
U. Tabori: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
C. Hawkins: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
D. Malkin: The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
P. N. Kongkham: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
W. A. Weiss: Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA
N. Jabado: McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada
J. T. Rutka: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
E. Bouffet: The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
J. O. Korbel: Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany
M. Lupien: Ontario Cancer Institute, Princess Margaret Cancer Centre–University Health Network, Toronto, Ontario M5G 1L7, Canada
K. D. Aldape: The University of Texas MD Anderson Cancer Center
G. D. Bader: The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada
R. Eils: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
P. Lichter: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
P. B. Dirks: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
S. M. Pfister: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
A. Korshunov: German Cancer Consortium (DKTK), Heidelberg 69120, Germany
M. D. Taylor: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada

Nature, 2014, vol. 506, issue 7489, 445-450

Abstract: Abstract Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Date: 2014
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DOI: 10.1038/nature13108

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