Cited by 608Glioma Diagnosis and TreatmentEpigenetics and DNA MethylationChromatin Remodeling and Cancer

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Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

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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.·2014·Nature

DOI 10.1038/nature13108PMC PMC4174313

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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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Williams, J., Xu, B., Putnam, D. K., Thrasher, A., Li, C., Yang, J., & Chen, X. (2021) · Figshare · doi:10.6084/m9.figshare.13605199
Additional file 1 of MethylationToActivity: a deep-learning framework that reveals promoter activity landscapes from DNA methylomes in individual tumors
Williams, J., Xu, B., Putnam, D. K., Thrasher, A., Li, C., Yang, J., & Chen, X. (2021) · Figshare · doi:10.6084/m9.figshare.13605193
Additional file 6 of DNA 5-hydroxymethylcytosine in pediatric central nervous system tumors may impact tumor classification and is a positive prognostic marker
Azizgolshani, N., Petersen, C. L., Chen, Y., Levy, J. J., Salas, L. A., Perreard, L., Nguyen, L. N., & Christensen, B. C. (2021) · Figshare · doi:10.6084/m9.figshare.16641870
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Takadera, M., Satomi, K., Szulzewsky, F., Cimino, P. J., Holland, E. C., Yamamoto, T., Ichimura, K., & Ozawa, T. (2020) · Figshare · doi:10.6084/m9.figshare.13278884
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One Flew Over the Cancer’s Nest
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Generation of a comprehensive epigenomic atlas in clear cell renal cell carcinoma informs kidney cancer progression and heritability
Alaiwi, S. A., Adib, E., Zhang, Z., Spisák, S., Prósz, A. G., Cordeiro, P., Zarif, T. E., Sztupinszki, Z. M., Nassar, A. H., Seo, J.-H., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.116968 · Cited by 1
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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
Publisher: Springer Science and Business Media LLC
Published: 2014-02
Volume: 506
Issue: 7489
Pages: 445-450
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13108
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

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Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

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