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Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Nature volume 506, pages 445–450 (2014)Cite this article

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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.

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Figure 1: Somatic SNVs are rare in the posterior fossa ependymoma genome.
Figure 2: DNA-methylation profiles suggest that group A ependymomas demonstrate a CpG island methylator phenotype.
Figure 3: Group A (CIMP+) and group B (CIMP−) ependymomas are distinguished by CpG-hypermethylated and H3K27-trimethylated genes related to PRC2 occupancy in ES cells.
Figure 4: Whole-genome bisulphite sequencing validates a CpG island methylator phenotype in group A ependymoma.
Figure 5: Modulation of H3K27 methylation has anti-neoplastic effects against group A ependymoma.

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Gene Expression Omnibus

Data deposits

Illumina 450K CpG Methylation array data, NimbleGen 385K CpG Island Plus array data, and ChIP-seq data have been deposited at the Gene Expression Omnibus (GEO: http://www.ncbi.nlm.nih.gov/geo/) as a GEO super-series under the accession number GSE43353. Whole-genome and whole-exome sequencing data have been deposited in the European Genome-Phenome Archive (EGA: https://www.ebi.ac.uk/ega/) hosted by the EBI, under the accession number EGAS00001000443.

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Acknowledgements

M.D.T. holds a Canadian Institutes of Health Research (CIHR) Clinician-Scientist Phase II Award, was a Sontag Foundation Distinguished Scholar, and is supported by The Garron Family Chair in Childhood Cancer Research. M.D.T. is supported by grants from the Cure Search Foundation, The Younger Foundation, the National Institutes of Health (R01CA148699 and R01CA159859), The Pediatric Brain Tumor Foundation, The Canadian Cancer Society, The Terry Fox Research Institute, and Brainchild. S.M., K.M.W. and A.D. are supported by Vanier Scholarships from CIHR. S.M. would like to thank K. Mack, R. Mack, S. Mack and K. Bertrand for their support of this project. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). This study was supported by grants from the Sander Foundation and DKTK (Molecular Diagnostics of Pediatric Malignancies). For technical support and expertise of next-generation sequencing efforts we thank the DKFZ Genomics and Proteomics Core Facility, The EMBL Genomics Core Facility, and The Centre for Applied Genomics (Toronto). We thank S. Archer for technical writing and C. Smith for artwork. We thank A. Wittmann, L. Sieber and L. Linke for clinical assistance.

Author information

Author notes

  1. S. C. Mack and H. Witt: These authors contributed equally to this work.

Authors and Affiliations

  1. Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada,

    S. C. Mack, X. Wang, M. Gallo, L. Garzia, K. Zayne, V. Ramaswamy, D. J. H. Shih, R. Head, M. Remke, C. C. Faria, M. Barszczyk, A. M. Dubuc, J. Peacock, K. C. Bertrand, S. Agnihotri, F. M. G. Cavalli, I. Clarke, K. Nethery-Brokx, X. Wu, Y. Yao, P. Sin-Chan, J. Zuccaro, L. Lau, S. Pereira, P. Castelo-Branco, S. W. Scherer, A. Huang, U. Tabori, C. Hawkins, P. N. Kongkham, J. T. Rutka, P. B. Dirks & M. D. Taylor

  2. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada,

    S. C. Mack, X. Wang, V. Ramaswamy, D. J. H. Shih, M. Remke, M. Barszczyk, A. M. Dubuc, J. Peacock, K. C. Bertrand, Y. Yao, C. Hawkins, P. N. Kongkham, J. T. Rutka, P. B. Dirks & M. D. Taylor

  3. Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada,

    S. C. Mack, P. N. Kongkham, J. T. Rutka, P. B. Dirks & M. D. Taylor

  4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany,

    H. Witt, D. T. W. Jones, M. Ryzhova, S. Stark, H. Seker-Cin, S. Hutter, P. Johann, S. Bender, T. Tzaridis, P. A. Northcott, M. Kool & S. M. Pfister

  5. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany,

    H. Witt, T. Milde, A. E. Kulozik, O. Witt & S. M. Pfister

  6. German Cancer Consortium (DKTK), Heidelberg 69120, Germany,

    H. Witt, R. M. Piro, L. Gu, A. M. Stütz, N. Jäger, D. T. W. Jones, M. Sill, M. Ryzhova, T. Zichner, S. Stark, H. Seker-Cin, S. Hutter, P. Johann, S. Bender, V. Hovestadt, T. Tzaridis, P. A. Northcott, T. Milde, A. E. Kulozik, A. von Deimling, O. Witt, M. Kool, R. Eils, P. Lichter, S. M. Pfister & A. Korshunov

  7. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,

    R. M. Piro, V. Hovestadt & P. Lichter

  8. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,

    L. Gu, N. Jäger & R. Eils

  9. Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada,

    S. Zuyderduyn & G. D. Bader

  10. Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany,

    A. M. Stütz, T. Zichner & J. O. Korbel

  11. Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, 03756, New Hampshire, USA

    X. Zhang

  12. Division of Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,

    M. Sill

  13. Department of Neurology, Harvard Medical School, Children’s Hospital Boston, MIT, Boston, Massachusetts 02115, USA,

    T. J. Pugh & S. L. Pomeroy

  14. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA

    K. M. Wani & K. D. Aldape

  15. Ontario Cancer Institute, Princess Margaret Cancer Centre–University Health Network, Toronto, Ontario M5G 1L7, Canada,

    S. D. Bailey & M. Lupien

  16. Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada,

    S. D. Bailey & M. Lupien

  17. Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, 19426, Pennsylvania, USA

    C. L. Creasy & S. K. Verma

  18. Department of Oncogenomics, Academic Medical Center, Amsterdam 1105, The Netherlands,

    J. Koster

  19. CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,

    T. Milde & O. Witt

  20. Department of Microbiology & Immunology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada,

    M. Hirst

  21. Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada,

    M. Hirst & M. A. Marra

  22. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada,

    M. A. Marra

  23. Department of Pediatrics and National Capital Consortium, Uniformed Services University, Bethesda, 20814, Maryland, USA

    S. S. Roberts

  24. Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, 84132, Utah, USA

    D. Fults

  25. Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy,

    L. Massimi

  26. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, 94305, California, USA

    Y. J. Cho

  27. Department of Pediatrics, Virginia Commonwealth, Richmond, 23298-0646, Virginia, USA

    T. Van Meter

  28. Department of Pathology, University of Warsaw, Children’s Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland,

    W. Grajkowska

  29. Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada,

    B. Lach

  30. Department of Neuropathology Ruprecht-Karls-University Heidelberg, Institute of Pathology, Heidelberg 69120, Germany,

    A. von Deimling

  31. University of Michigan Cell and Developmental Biology, Ann Arbor, 48109-2200, Michigan, USA

    X. Fan & A. Korshunov

  32. Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    X. Fan & K. M. Muraszko

  33. Department of Neurosurgery, University of California San Francisco, San Francisco, 94143-0112, California, USA

    N. Gupta

  34. Departments of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA,

    J. Phillips & W. A. Weiss

  35. Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,

    A. Huang, U. Tabori & E. Bouffet

  36. Department of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada,

    D. Malkin

  37. Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada,

    N. Jabado

  38. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada,

    M. Lupien

  39. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada,

    P. B. Dirks

  40. CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany,

    A. Korshunov

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Contributions

S.C.M., H.W., M.D.T., A.K. and S.M.P. conceived and led the study. S.C.M. performed sample preparation, data acquisition and bioinformatic analysis related to DNA methylation, ChIP-seq and transcriptional profiling experiments. S.C.M. also performed western blot analysis and contributed to in vitro and in vivo experiments. H.W. led whole-genome sequencing, whole-exome sequencing and whole-genome bisulphite sequencing efforts, with analytical support from R.M.P., L. Gu., N. Jäger, D.T.W.J., S.S., S.H., T.Z., A.M.S., T.J.P., M.S., H.S.-C., T.T., V.H. and J.O.K. S.Z. and G.D.B. developed and applied pathway analysis methods for all data sets in this study. K.N.-B., M.G., L. Garzia, K.Z., X. Wang, M.B., S.B., P.J., X. Wu, K.C.B., T.M., J.Z., P.S.-C., C.C.F., P.C.-B., Y.Y. and S.A. performed in vitro, in vivo and molecular/biochemical experiments central to the project. DNA methylation and ChIP-seq bioinformatic analysis and experimental design were supported by X.Z., V.R., P.N.K., A.M.D., P.A.N., D.J.H.S., J.P., M. Remke, F.M.G.C., L.L., S.P., S.W.S., S.D.B., M.G., J.K., I.C., R.H. and P.B.D., developed and characterized ependymoma primary cultures, and assisted with in vitro and in vivo experiments. C.L.C. and S.K.V. developed the EZH2 compounds and provided inhibitors for experimentation. S.S.R., L.M., Y.J.C., T.V.M., W.G., B.L., M. Ryzhova, A.K., N.G., J.P., K.W. and K.D.A. provided patient samples and clinical details that made this study possible. M.H., M.A.M., M.L., D.F., A.E.K., A.v.D., O.W., D.M., X.F., K.M.M., M.K., S.L.P., E.B., W.A.W., A.H., U.T., C.H., J.T.R., N. Jabado, J.O.K., R.E., P.L., G.D.B., K.D.A., P.B.D. and S.M.P. provided valuable input regarding study design, data analysis and interpretation of results. M.D.T., S.C.M., H.W., A.K. and S.M.P. wrote the manuscript. M.D.T. and S.M.P. provided financial and technical infrastructure and oversaw the study. M.D.T. and A.K. are joint senior authors and project co-leaders.

Corresponding authors

Correspondence to A. Korshunov or M. D. Taylor.

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The authors declare no competing financial interests.

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Mack, S., Witt, H., Piro, R. et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450 (2014). https://doi.org/10.1038/nature13108

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