Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

doi:10.1038/nature13108

. 2014 Feb 27;506(7489):445-50.

doi: 10.1038/nature13108. Epub 2014 Feb 19.

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

S C Mack¹, H Witt², R M Piro³, L Gu⁴, S Zuyderduyn⁵, A M Stütz⁶, X Wang⁷, M Gallo⁸, L Garzia⁸, K Zayne⁸, X Zhang⁹, V Ramaswamy⁷, N Jäger⁴, D T W Jones¹⁰, M Sill¹¹, T J Pugh¹², M Ryzhova¹⁰, K M Wani¹³, D J H Shih⁷, R Head⁸, M Remke⁷, S D Bailey¹⁴, T Zichner⁶, C C Faria⁸, M Barszczyk⁷, S Stark¹⁰, H Seker-Cin¹⁰, S Hutter¹⁰, P Johann¹⁰, S Bender¹⁰, V Hovestadt³, T Tzaridis¹⁰, A M Dubuc⁷, P A Northcott¹⁰, J Peacock⁷, K C Bertrand⁷, S Agnihotri⁸, F M G Cavalli⁸, I Clarke⁸, K Nethery-Brokx⁸, C L Creasy¹⁵, S K Verma¹⁵, J Koster¹⁶, X Wu⁸, Y Yao⁷, T Milde¹⁷, P Sin-Chan⁸, J Zuccaro⁸, L Lau⁸, S Pereira⁸, P Castelo-Branco⁸, M Hirst¹⁸, M A Marra¹⁹, S S Roberts²⁰, D Fults²¹, L Massimi²², Y J Cho²³, T Van Meter²⁴, W Grajkowska²⁵, B Lach²⁶, A E Kulozik²⁷, A von Deimling²⁸, O Witt¹⁷, S W Scherer⁸, X Fan²⁹, K M Muraszko³⁰, M Kool¹⁰, S L Pomeroy¹², N Gupta³¹, J Phillips³², A Huang³³, U Tabori³³, C Hawkins⁷, D Malkin³⁴, P N Kongkham³⁵, W A Weiss³², N Jabado³⁶, J T Rutka³⁵, E Bouffet³⁷, J O Korbel³⁸, M Lupien³⁹, K D Aldape¹³, G D Bader⁵, R Eils⁴, P Lichter³, P B Dirks⁴⁰, S M Pfister⁴¹, A Korshunov⁴², M D Taylor³⁵

Affiliations

¹ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4].
² 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [4].
³ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁴ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁵ Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada.
⁶ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany.
⁷ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
⁸ Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
⁹ Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
¹⁰ 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
¹¹ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
¹² Department of Neurology, Harvard Medical School, Children's Hospital Boston, MIT, Boston, Massachusetts 02115, USA.
¹³ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
¹⁴ 1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada.
¹⁵ Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.
¹⁶ Department of Oncogenomics, Academic Medical Center, Amsterdam 1105, The Netherlands.
¹⁷ 1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [3] CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
¹⁸ 1] Centre for High-Throughput Biology, Department of Microbiology & Immunology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada [2] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
¹⁹ 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
²⁰ Department of Pediatrics and National Capital Consortium, Uniformed Services University, Bethesda, Maryland 20814, USA.
²¹ Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
²² Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy.
²³ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
²⁴ Department of Pediatrics, Virginia Commonwealth, Richmond, Virginia 23298-0646, USA.
²⁵ Department of Pathology, University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland.
²⁶ Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada.
²⁷ 1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
²⁸ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Department of Neuropathology Ruprecht-Karls-University Heidelberg, Institute of Pathology, Heidelberg 69120, Germany.
²⁹ 1] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [2] Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
³⁰ Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
³¹ Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143-0112, USA.
³² Departments of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA.
³³ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
³⁴ Department of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
³⁵ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
³⁶ Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada.
³⁷ Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
³⁸ Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany.
³⁹ 1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
⁴⁰ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
⁴¹ 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
⁴² 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [3] CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

PMID: 24553142
PMCID: PMC4174313
DOI: 10.1038/nature13108

Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

S C Mack et al. Nature. 2014.

. 2014 Feb 27;506(7489):445-50.

doi: 10.1038/nature13108. Epub 2014 Feb 19.

Authors

Affiliations

¹ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4].
² 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [4].
³ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁴ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁵ Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada.
⁶ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany.
⁷ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
⁸ Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
⁹ Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
¹⁰ 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
¹¹ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
¹² Department of Neurology, Harvard Medical School, Children's Hospital Boston, MIT, Boston, Massachusetts 02115, USA.
¹³ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
¹⁴ 1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada.
¹⁵ Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA.
¹⁶ Department of Oncogenomics, Academic Medical Center, Amsterdam 1105, The Netherlands.
¹⁷ 1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [3] CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
¹⁸ 1] Centre for High-Throughput Biology, Department of Microbiology & Immunology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada [2] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
¹⁹ 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada.
²⁰ Department of Pediatrics and National Capital Consortium, Uniformed Services University, Bethesda, Maryland 20814, USA.
²¹ Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
²² Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy.
²³ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
²⁴ Department of Pediatrics, Virginia Commonwealth, Richmond, Virginia 23298-0646, USA.
²⁵ Department of Pathology, University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland.
²⁶ Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada.
²⁷ 1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
²⁸ 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Department of Neuropathology Ruprecht-Karls-University Heidelberg, Institute of Pathology, Heidelberg 69120, Germany.
²⁹ 1] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [2] Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
³⁰ Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
³¹ Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143-0112, USA.
³² Departments of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA.
³³ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
³⁴ Department of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
³⁵ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
³⁶ Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada.
³⁷ Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
³⁸ Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany.
³⁹ 1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
⁴⁰ 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
⁴¹ 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
⁴² 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [3] CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

PMID: 24553142
PMCID: PMC4174313
DOI: 10.1038/nature13108

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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Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Figure 1. Somatic SNVs are rare in the posterior fossa ependymoma genome**
a, Summary of clinical and genomic details of PF ependymomas stratified according to group A and group B ependymoma (Wilcoxon rank-sum test). CNV, copy number variation; NA, not available; NS, not significant; WES, whole-exome sequencing; WGS, whole-genome sequencing. b, Bar graphs summarizing the numbers and frequencies of SNVs detected by whole-genome and whole-exome sequencing of PF ependymomas. c, Comparison of numbers of significant and recurrently mutated genes, and mutation rates, in several whole-genome and whole-exome sequencing studies of adult and paediatric cancers (false discovery rate (FDR) <0.1).

**Figure 2. DNA-methylation profiles suggest that group A ependymomas demonstrate a CpG island methylator phenotype**
a, Unsupervised hierarchical clustering of 79 ependymoma DNA-methylation profiles. SP, spinal cord; ST, supratentorial. b, Heatmap of 48 PF ependymoma DNA-methylation profiles. Group A and group B clinical differences were assessed using a two-sided Fisher’s exact test. c, Volcano plot comparing the number of significant methylated CpG sites between group A and group B (P < 0.05, Wilcoxon rank-sum test, FDR-corrected). d, e, Differences in the number of methylated genes (d) and methylated and silenced genes (e) in group A versus group B (P < 0.0001, binomial distribution test).

**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**
a, b, CpG-methylated pathways in group A (CIMP⁺) and group B (CIMP⁻) ependymomas in a discovery (a) and validation (b) cohort. c, Differential H3K27me3 binding sites distinguishing group A and group B (P < 0.01 (MACSv2.0), P < 0.05 (R:DiffBind)). d, e, Venn diagrams comparing group A and group B H3K27me3 genes with ES cell PRC2 genes (d) and group A H3K27me3 and DNA-hypermethylated genes with ES cell H3K27me3 genes (e). f, Group B H3K27me3 and DNA-hypermethylated genes with ES cell H3K27me3 genes (binomial distribution test).

**Figure 4. Whole-genome bisulphite sequencing validates a CpG island methylator phenotype in group A ependymoma**
a, b, Heatmap of DNA methylation at CpG islands (a) and repetitive regions (b) in group A (CIMP⁺) versus group B (CIMP⁻). NB, normal brain. c, d, Proportion of hypermethylated versus hypomethylated regions at CpG islands (c) and repetitive elements (d) in group A and group B (P <2.2 × 10⁻¹⁶, binomial distribution test). LINE, long interspersed nuclear elements; LTR, long terminal repeats; SINE, short interspersed nuclear elements. e, f, Top 10 pathways upregulated (e) and differentially expressed (f) upon DAC treatment of E517-PF2 and E520-PF1 (P < 0.0001, binomial distribution test). g, Survival analysis of E478-ST2, E479-ST1, E517-PF2 and E520-PF1 cells treated for 7 days with DAC (P =0.05, two-sided t-test, error bars, s.e.m.; technical (n =6) over biological (n =2)). h, Limiting dilution assay of zero passage group A cells treated for 2 weeks with DAC (P =4.18 × 10⁻¹⁰, chi-squared test). DMSO, dimethylsulphoxide.

**Figure 5. Modulation of H3K27 methylation has anti-neoplastic effects against group A ependymoma**
a, Survival of E479-ST1, E478-ST2, E520-PF1 and E517-PF2 cells treated for 7 days with DZNep (P < 0.0001, two-sided t-test, error bars =s.e.m., biological (n =3)). b, EZH2, H3K27me3, H3K4me3 and cleaved-PARP protein expression in E520-PF1 and E479-ST1 cells treated for 7 days with DZNep (500 nM). c, E520-PF1 flank tumour volumes following treatment with DZNep (P =0.0087, Wilcoxon-test, error bars =s.d.). d, Survival of E520-PF1 PF tumour-bearing mice treated with DZNep (P =0.033, log-rank test). e, f, Top 10 pathways upregulated (e) and differentially expressed (f) upon treatment of E517 and E520 with GSK343. g, Cell proliferation of E520-PF1 and E479-ST1 cells treated for 11 days with GSK343 (active inhibitor) or GSK669 (inactive inhibitor) (P =0.0022, two-sided t-test, error bars =s.e.m., technical (n =9) over biological (n =3)). h, Limiting dilution assay of passage zero group A cells treated for 2 weeks with GSK343 (P =2.83× 10⁻⁵, chi-square-test). HCP, high-CpG-density promoter.

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Comment in

Cancer: Tumours outside the mutation box.
Versteeg R. Versteeg R. Nature. 2014 Feb 27;506(7489):438-9. doi: 10.1038/nature13061. Epub 2014 Feb 19. Nature. 2014. PMID: 24553138 No abstract available.

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References

1. Taylor MD, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005;8:323–335. - PubMed
1. Merchant TE, et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 2009;10:258–266. - PMC - PubMed
1. Bouffet E, Foreman N. Chemotherapy for intracranial ependymomas. Childs Nerv Syst. 1999;15:563–570. - PubMed
1. Bouffet E, et al. Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys. 2012;83:1541–1548. - PubMed
1. Johnson RA, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature. 2010;466:632–636. - PMC - PubMed

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[1] Taylor MD, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005;8:323–335. - PubMed

[2] Taylor MD, et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005;8:323–335. - PubMed

[3] Merchant TE, et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 2009;10:258–266. - PMC - PubMed

[4] Merchant TE, et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 2009;10:258–266. - PMC - PubMed

[5] Bouffet E, Foreman N. Chemotherapy for intracranial ependymomas. Childs Nerv Syst. 1999;15:563–570. - PubMed

[6] Bouffet E, Foreman N. Chemotherapy for intracranial ependymomas. Childs Nerv Syst. 1999;15:563–570. - PubMed

[7] Bouffet E, et al. Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys. 2012;83:1541–1548. - PubMed

[8] Bouffet E, et al. Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys. 2012;83:1541–1548. - PubMed

[9] Johnson RA, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature. 2010;466:632–636. - PMC - PubMed

[10] Johnson RA, et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature. 2010;466:632–636. - PMC - PubMed

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Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

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Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

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