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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Gene Expression Omnibus
Illumina 450K CpG Methylation array data, NimbleGen 385K CpG Island Plus array data, and ChIP-seq data have been deposited at the Gene Expression Omnibus (GEO: http://www.ncbi.nlm.nih.gov/geo/) as a GEO super-series under the accession number GSE43353. Whole-genome and whole-exome sequencing data have been deposited in the European Genome-Phenome Archive (EGA: https://www.ebi.ac.uk/ega/) hosted by the EBI, under the accession number EGAS00001000443.
M.D.T. holds a Canadian Institutes of Health Research (CIHR) Clinician-Scientist Phase II Award, was a Sontag Foundation Distinguished Scholar, and is supported by The Garron Family Chair in Childhood Cancer Research. M.D.T. is supported by grants from the Cure Search Foundation, The Younger Foundation, the National Institutes of Health (R01CA148699 and R01CA159859), The Pediatric Brain Tumor Foundation, The Canadian Cancer Society, The Terry Fox Research Institute, and Brainchild. S.M., K.M.W. and A.D. are supported by Vanier Scholarships from CIHR. S.M. would like to thank K. Mack, R. Mack, S. Mack and K. Bertrand for their support of this project. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). This study was supported by grants from the Sander Foundation and DKTK (Molecular Diagnostics of Pediatric Malignancies). For technical support and expertise of next-generation sequencing efforts we thank the DKFZ Genomics and Proteomics Core Facility, The EMBL Genomics Core Facility, and The Centre for Applied Genomics (Toronto). We thank S. Archer for technical writing and C. Smith for artwork. We thank A. Wittmann, L. Sieber and L. Linke for clinical assistance.
This file contains Supplementary Tables 1-23.
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Acta Neuropathologica (2018)