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. HeadM. 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, Yoon-Jae 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

Research output: Contribution to journalArticle

297 Citations (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.

Original languageEnglish (US)
Pages (from-to)445-450
Number of pages6
JournalNature
Volume506
Issue number7489
DOIs
StatePublished - Feb 21 2014
Externally publishedYes

Fingerprint

Ependymoma
Rhombencephalon
Epigenomics
CpG Islands
Methylation
Polycomb Repressive Complex 2
Nucleotides
Exome
Phenotype
Mutation Rate
Brain Neoplasms
Nervous System
Genome
Radiation
Pediatrics
Gene Expression
Drug Therapy
DNA
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

MacK, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., ... Taylor, M. D. (2014). Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature, 506(7489), 445-450. https://doi.org/10.1038/nature13108

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. / MacK, S. C.; Witt, H.; Piro, R. M.; Gu, L.; Zuyderduyn, S.; Stütz, A. M.; Wang, X.; Gallo, M.; Garzia, L.; Zayne, K.; Zhang, X.; Ramaswamy, V.; Jäger, N.; Jones, D. T.W.; Sill, M.; Pugh, T. J.; Ryzhova, M.; Wani, K. M.; Shih, D. J.H.; Head, R.; Remke, M.; Bailey, S. D.; Zichner, T.; Faria, C. C.; Barszczyk, M.; Stark, S.; Seker-Cin, H.; Hutter, S.; Johann, P.; Bender, S.; Hovestadt, V.; Tzaridis, T.; Dubuc, A. M.; Northcott, P. A.; Peacock, J.; Bertrand, K. C.; Agnihotri, S.; Cavalli, F. M.G.; Clarke, I.; Nethery-Brokx, K.; Creasy, C. L.; Verma, S. K.; Koster, J.; Wu, X.; Yao, Y.; Milde, T.; Sin-Chan, P.; Zuccaro, J.; Lau, L.; Pereira, S.; Castelo-Branco, P.; Hirst, M.; Marra, M. A.; Roberts, S. S.; Fults, D.; Massimi, L.; Cho, Yoon-Jae; Van Meter, T.; Grajkowska, W.; Lach, B.; Kulozik, A. E.; Von Deimling, A.; Witt, O.; Scherer, S. W.; Fan, X.; Muraszko, K. M.; Kool, M.; Pomeroy, S. L.; Gupta, N.; Phillips, J.; Huang, A.; Tabori, U.; Hawkins, C.; Malkin, D.; Kongkham, P. N.; Weiss, W. A.; Jabado, N.; Rutka, J. T.; Bouffet, E.; Korbel, J. O.; Lupien, M.; Aldape, K. D.; Bader, G. D.; Eils, R.; Lichter, P.; Dirks, P. B.; Pfister, S. M.; Korshunov, A.; Taylor, M. D.

In: Nature, Vol. 506, No. 7489, 21.02.2014, p. 445-450.

Research output: Contribution to journalArticle

MacK, SC, Witt, H, Piro, RM, Gu, L, Zuyderduyn, S, Stütz, AM, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, DTW, Sill, M, Pugh, TJ, Ryzhova, M, Wani, KM, Shih, DJH, Head, R, Remke, M, Bailey, SD, Zichner, T, Faria, CC, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, AM, Northcott, PA, Peacock, J, Bertrand, KC, Agnihotri, S, Cavalli, FMG, Clarke, I, Nethery-Brokx, K, Creasy, CL, Verma, SK, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, MA, Roberts, SS, Fults, D, Massimi, L, Cho, Y-J, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, AE, Von Deimling, A, Witt, O, Scherer, SW, Fan, X, Muraszko, KM, Kool, M, Pomeroy, SL, Gupta, N, Phillips, J, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, PN, Weiss, WA, Jabado, N, Rutka, JT, Bouffet, E, Korbel, JO, Lupien, M, Aldape, KD, Bader, GD, Eils, R, Lichter, P, Dirks, PB, Pfister, SM, Korshunov, A & Taylor, MD 2014, 'Epigenomic alterations define lethal CIMP-positive ependymomas of infancy', Nature, vol. 506, no. 7489, pp. 445-450. https://doi.org/10.1038/nature13108
MacK SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014 Feb 21;506(7489):445-450. https://doi.org/10.1038/nature13108
MacK, S. C. ; Witt, H. ; Piro, R. M. ; Gu, L. ; Zuyderduyn, S. ; Stütz, A. M. ; Wang, X. ; Gallo, M. ; Garzia, L. ; Zayne, K. ; Zhang, X. ; Ramaswamy, V. ; Jäger, N. ; Jones, D. T.W. ; Sill, M. ; Pugh, T. J. ; Ryzhova, M. ; Wani, K. M. ; Shih, D. J.H. ; Head, R. ; Remke, M. ; Bailey, S. D. ; Zichner, T. ; Faria, C. C. ; Barszczyk, M. ; Stark, S. ; Seker-Cin, H. ; Hutter, S. ; Johann, P. ; Bender, S. ; Hovestadt, V. ; Tzaridis, T. ; Dubuc, A. M. ; Northcott, P. A. ; Peacock, J. ; Bertrand, K. C. ; Agnihotri, S. ; Cavalli, F. M.G. ; Clarke, I. ; Nethery-Brokx, K. ; Creasy, C. L. ; Verma, S. K. ; Koster, J. ; Wu, X. ; Yao, Y. ; Milde, T. ; Sin-Chan, P. ; Zuccaro, J. ; Lau, L. ; Pereira, S. ; Castelo-Branco, P. ; Hirst, M. ; Marra, M. A. ; Roberts, S. S. ; Fults, D. ; Massimi, L. ; Cho, Yoon-Jae ; Van Meter, T. ; Grajkowska, W. ; Lach, B. ; Kulozik, A. E. ; Von Deimling, A. ; Witt, O. ; Scherer, S. W. ; Fan, X. ; Muraszko, K. M. ; Kool, M. ; Pomeroy, S. L. ; Gupta, N. ; Phillips, J. ; Huang, A. ; Tabori, U. ; Hawkins, C. ; Malkin, D. ; Kongkham, P. N. ; Weiss, W. A. ; Jabado, N. ; Rutka, J. T. ; Bouffet, E. ; Korbel, J. O. ; Lupien, M. ; Aldape, K. D. ; Bader, G. D. ; Eils, R. ; Lichter, P. ; Dirks, P. B. ; Pfister, S. M. ; Korshunov, A. ; Taylor, M. D. / Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. In: Nature. 2014 ; Vol. 506, No. 7489. pp. 445-450.
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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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TY - JOUR

T1 - Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

AU - MacK, S. C.

AU - Witt, H.

AU - Piro, R. M.

AU - Gu, L.

AU - Zuyderduyn, S.

AU - Stütz, A. M.

AU - Wang, X.

AU - Gallo, M.

AU - Garzia, L.

AU - Zayne, K.

AU - Zhang, X.

AU - Ramaswamy, V.

AU - Jäger, N.

AU - Jones, D. T.W.

AU - Sill, M.

AU - Pugh, T. J.

AU - Ryzhova, M.

AU - Wani, K. M.

AU - Shih, D. J.H.

AU - Head, R.

AU - Remke, M.

AU - Bailey, S. D.

AU - Zichner, T.

AU - Faria, C. C.

AU - Barszczyk, M.

AU - Stark, S.

AU - Seker-Cin, H.

AU - Hutter, S.

AU - Johann, P.

AU - Bender, S.

AU - Hovestadt, V.

AU - Tzaridis, T.

AU - Dubuc, A. M.

AU - Northcott, P. A.

AU - Peacock, J.

AU - Bertrand, K. C.

AU - Agnihotri, S.

AU - Cavalli, F. M.G.

AU - Clarke, I.

AU - Nethery-Brokx, K.

AU - Creasy, C. L.

AU - Verma, S. K.

AU - Koster, J.

AU - Wu, X.

AU - Yao, Y.

AU - Milde, T.

AU - Sin-Chan, P.

AU - Zuccaro, J.

AU - Lau, L.

AU - Pereira, S.

AU - Castelo-Branco, P.

AU - Hirst, M.

AU - Marra, M. A.

AU - Roberts, S. S.

AU - Fults, D.

AU - Massimi, L.

AU - Cho, Yoon-Jae

AU - Van Meter, T.

AU - Grajkowska, W.

AU - Lach, B.

AU - Kulozik, A. E.

AU - Von Deimling, A.

AU - Witt, O.

AU - Scherer, S. W.

AU - Fan, X.

AU - Muraszko, K. M.

AU - Kool, M.

AU - Pomeroy, S. L.

AU - Gupta, N.

AU - Phillips, J.

AU - Huang, A.

AU - Tabori, U.

AU - Hawkins, C.

AU - Malkin, D.

AU - Kongkham, P. N.

AU - Weiss, W. A.

AU - Jabado, N.

AU - Rutka, J. T.

AU - Bouffet, E.

AU - Korbel, J. O.

AU - Lupien, M.

AU - Aldape, K. D.

AU - Bader, G. D.

AU - Eils, R.

AU - Lichter, P.

AU - Dirks, P. B.

AU - Pfister, S. M.

AU - Korshunov, A.

AU - Taylor, M. D.

PY - 2014/2/21

Y1 - 2014/2/21

N2 - 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.

AB - 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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