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Epigenomic alterations define lethal CIMP-positive ependymomas of infancy
Open accessAbstract
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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Metadata
- Authors
- 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, Y. J., 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.
- Affiliations
- University of Toronto (CA)
- German Cancer Research Center (DE)
- European Molecular Biology Laboratory (DE)
- Hospital for Sick Children (CA)
- Dartmouth–Hitchcock Medical Center (US)
- Boston Children's Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Ontario Institute for Cancer Research (CA)
- GlaxoSmithKline (United States) (US)
- BC Cancer Agency (CA)
- Uniformed Services University of the Health Sciences (US)
- University of Utah (US)
- Agostino Gemelli University Polyclinic (IT)
- Stanford Medicine (US)
- Children's Memorial Health Institute (PL)
- Hamilton General Hospital (CA)
- Heidelberg University (DE)
- University of Michigan (US)
- University of California, San Francisco (US)
- McGill University Health Centre (CA)
- Corresponding author
- Korshunov, A.
- Taylor, M. D.
- ORCID
- Mack, S. C.
- Witt, H.
- Piro, R. M.
- Gu, L.
- Stütz, A. M.
- Wang, X.
- Gallo, M.
- Garzia, L.
- Zhang, X.
- Ramaswamy, V.
- Jäger, N.
- Jones, D. T. W.
- Sill, M.
- Pugh, T. J.
- Ryzhova, M.
- Wani, K. M.
- Shih, D. J. H.
- Remke, M.
- Bailey, S. D.
- Zichner, T.
- Faria, C. C.
- Barszczyk, M.
- Hutter, S.
- Johann, P.
- Hovestadt, V.
- Tzaridis, T.
- Dubuc, A. M.
- Northcott, P. A.
- Bertrand, K. C.
- Agnihotri, S.
- Cavalli, F. M. G.
- Creasy, C. L.
- Verma, S. K.
- Wu, X.
- Yao, Y.
- Milde, T.
- Zuccaro, J.
- Lau, L.
- Pereira, S.
- Hirst, M.
- Marra, M. A.
- Roberts, S. S.
- Fults, D.
- Massimi, L.
- Cho, Y. J.
- Grajkowska, W.
- Lach, B.
- Kulozik, A. E.
- 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.
- 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.
- Venue
- Nature
- Published
- 2014-02
- Volume
- 506
- Issue
- 7489
- Pages
- 445-450
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4174313
- OpenAlex
- W2113432767
- Cited by
- 607
- References
- 50
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 30 · 2023: 29 · 2022: 37 · 2021: 51 · 2020: 56 · 2019: 55 · 2018: 68 · 2017: 64 · 2016: 73 · 2015: 57 · 2014: 40
- FWCI
- 39.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Pediatric Brain Tumor Foundation
- CureSearch for Children's Cancer
- Deutsches Krebsforschungszentrum
- Government of Ontario
- Bundesministerium für Bildung und Forschung (01KU1201A, 01GS0883)
- Terry Fox Research Institute
- Deutsche Krebshilfe (109252)
- Deutschen Konsortium für Translationale Krebsforschung
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute (R01CA148699, R01CA148621, R01CA121941, R01CA163737, R01CA159859, P30CA016672, P50CA097257)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- ependymoma, CpG island methylator phenotype, pediatric brain tumors, C11orf95-RELA fusion, chromothripsis, NF-κB signaling, H3K27me3, polycomb repressive complex 2, DNA methylation, EZH2 inhibitors, epigenetic therapy, tumor suppressor
- MeSH terms
- Animals, Brain Neoplasms, Ependymoma, Female, Histones, Humans, Infant, Mutation, Phenotype, Prognosis, Rhombencephalon, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, CpG Islands, DNA Methylation, Gene Silencing, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Epigenomics, Polycomb Repressive Complex 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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