Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Luca Massimi, 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. ShihR. 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, 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, M. D. Taylor

Risultato della ricerca: Contributo in rivistaArticolo in rivista

367 Citazioni (Scopus)

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. © 2014 Macmillan Publishers Limited.
Lingua originaleEnglish
pagine (da-a)445-450
Numero di pagine6
RivistaNature
Volume506
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Animals
  • Brain Neoplasms
  • CpG Islands
  • DNA Methylation
  • Embryonic Stem Cells
  • Ependymoma
  • Epigenesis, Genetic
  • Epigenomics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Histones
  • Humans
  • Infant
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Multidisciplinary
  • Mutation
  • Phenotype
  • Polycomb Repressive Complex 2
  • Prognosis
  • Rhombencephalon
  • Xenograft Model Antitumor Assays

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