EPN-34EPIGENOMIC ANALYSIS OF EPENDYMAL TUMORS IDENTIFIES SUBGROUP SPECIFIC ENHANCERS CONTROLLING DISTINCT REGULATORY CIRCUITRIES
Authors: Lukas Chavez, Kristian W. Pajtler, Serap Erkek, Hendrik Witt, Susanne Gröbner, Zhiqin Huang, Mark Zapatka, Volker Hovestadt, David T. W. Jones, Jan O. Korbel, Peter Lichter, Stefan M. Pfister, Marcel Kool
Journal: Neuro-Oncology (2016)

EPN-34. EPIGENOMIC ANALYSIS OF EPENDYMAL TUMORS IDENTIFIES SUBGROUP SPECIFIC ENHANCERS CONTROLLING DISTINCT REGULATORY CIRCUITRIES Lukas Chavez1,2, Kristian W. Pajtler1,2, Serap Erkek1,4, Hendrik Witt1,2, Susanne Grobner1,2, Zhiqin Huang5, Mark Zapatka5, Volker Hovestadt5, David T. W. Jones1,2, Jan O. Korbel4, Peter Lichter5, Stefan M. Pfister1,2, and Marcel Kool1,2; Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany; Genome Biology Unit, European Molecular Laboratory (EMBL), Heidelberg, Germany; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neuropathology, University of Heidelberg, Heidelberg, Germany RecentmolecularclassificationeffortsusingDNAmethylationprofiles from 500 ependymal tumors revealed six distinct intracranial molecular subgroups, three in the posterior fossa and three in the supratentorial region. The vast majorityofhigh-riskpatients, forwhomeffective therapeutic conceptsaredesperately needed, were restricted to posterior fossa Group A ependymomas, PF-EPN-A, and to the largest group of supratentorial ependymomas, ST-EPN-RELA, harboring fusions to the principal effector of canonical NF-kB signaling. The current inability to effectively target alterations of the NF-kB pathway in ST-EPN-RELA and the lackof recurrent mutations oralternative distinctdriver events inPF-EPN-A andmostof the other subgroupshave so far hindered the development of novel (subgroup-specific) treatment strategies. To get a better understanding what is driving these tumors, we have used H3K27acChIP-Seq, integrated with tissue-matched DNA methylation, DNAand RNA-sequencing, to analyze the active cis-regulatory landscape across 24 individual tumors from all six intracranial molecular subgroups. Quantitative comparisons of H3K27ac enrichments across subgroups identified common and subgroup-specific enhancers as well as super-enhancers, thereby confirming inter-subgroup heterogeneity. Systematic correlation analyses between enhancer activity and gene expression within topologically associated domains, combined with computational analyses of transcription factor binding sites at enhancer loci, identified regulatory circuitries governing distinct transcriptional landscapes that are likely responsible for subgroup divergence. Our integrated analysis of enhancer elements in primary human tumors reveals novel insights into the genome-wide cis-regulatory architecture of ependymoma subgroups and their potential origins and may have relevant implications for future, possibly lineage-specific, therapeutic targeting approaches. Neuro-Oncology 18:iii30–iii39, 2016. doi:10.1093/neuonc/now070.33 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.