EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100396624EGA dataset EGAD00001003966EGAGenomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling.Mack Stephen C SC, Pajtler Kristian W KW, Chavez Lukas L, Okonechnikov Konstantin K, Bertrand Kelsey C KC, Wang Xiuxing X, Erkek Serap S, Federation Alexander A, Song Anne A, Lee Christine C, Wang Xin X, McDonald Laura L, Morrow James J JJ, Saiakhova Alina A, Sin-Chan Patrick P, Wu Qiulian Q, Michaelraj Kulandaimanuvel Antony KA, Miller Tyler E TE, Hubert Christopher G CG, Ryzhova Marina M, Garzia Livia L, Donovan Laura L, Dombrowski Stephen S, Factor Daniel C DC, Luu Betty B, Valentim Claudia L L CLL, Gimple Ryan C RC, Morton Andrew A, Kim Leo L, Prager Briana C BC, Lee John J Y JJY, Wu Xiaochong X, Zuccaro Jennifer J, Thompson Yuan Y, Holgado Borja L BL, Reimand Jüri J, Ke Susan Q SQ, Tropper Adam A, Lai Sisi S, Vijayarajah Senthuran S, Doan Sylvia S, Mahadev Vaidehi V, Miñan Ana Fernandez AF, Gröbner Susanne N SN, Lienhard Matthias M, Zapatka Marc M, Huang Zhiqin Z, Aldape Kenneth D KD, Carcaboso Angel M AM, Houghton Peter J PJ, Keir Stephen T ST, Milde Till T, Witt Hendrik H, Li Yan Y, Li Chao-Jun CJ, Bian Xiu-Wu XW, Jones David T W DTW, Scott Ian I, Singh Sheila K SK, Huang Annie A, Dirks Peter B PB, Bouffet Eric E, Bradner James E JE, Ramaswamy Vijay V, Jabado Nada N, Rutka James T JT, Northcott Paul A PA, Lupien Mathieu M, Lichter Peter P, Korshunov Andrey A, Scacheri Peter C PC, Pfister Stefan M SM, Kool Marcel M, Taylor Michael D MD, Rich Jeremy N JNVasp, VASP, DmelCG15112, ENHANCER OF ATNSI ACTIVITY, Data Set, MENA, NDPP1, l(2)02029, Enb, enb, ENA, Ena, CG15112, 2018., ENA/VASPglioblastoma multiforme, Clear Cell Ependymoma, Anaplastic Ependymomas, oligodendroglioma, WHO grade II ependymal tumour, familial, astrocytoma, clear cell ependymoma (histologic variant), papillary ependymoma (histologic variant), subependymoma, benign, Anaplastic, Cellular Ependymoma, WHO grade II ependymal neoplasm, Papillary, Myxopapillary, Papillary Ependymoma, tanycytic ependymoma (histologic variant), Papillary., ependymoma, Ependymomas, Myxopapillary Ependymomas, Papillary Ependymomas, Myxopapillary Ependymoma, Anaplastic Ependymoma, glioma of brain, WHO grade II ependymal tumor, EpendymomaRNA, Data Set, RNA Sequence Determination, Edg, Analyses, instrument, Determination, RNA Sequence Determinations, Sequence Determination, RNA Sequence, instrument configuration, HardwareType, Sequence Determinations, Client, Sequencing, sample population, Determinations, hardware, RNA Sequence Analyses, Patient, HHT1., Clients, RNA Sequence Analysis, sample, RNA Sequencing, Analysis, ORW1, other neoplasm, END, Sequence Analysesoligodendroglioma, YAP65, scale tissue, Ribonucleic, Materials, insensitive, Prospecting, Laboratory, Age-at-Onset, neutral endopeptidase, acetylglucosaminyltransferase-like protein, neoplasia, Mus domesticus, Mbp1, Yap65, Tumor, clefted, House Mouse, Xrel1, Mutations, posterior, Drug Prospecting, concavities, Papillary Ependymoma, Myxopapillary Ependymomas, synganglion, Transforming, myd, Non Polyadenylated, hereditary., glioma of brain, Chromatins, RNA Gene Products, treatment, increased, like-acetylglucosaminyltransferase, Yap, YAP, cell process disease, tumor disease, plant peltate hair, neoplasm (disease), SFE, Age of onset, Mbp-1, Swiss Mice, benign, suprasegmental levels of nervous system, Cellular Ependymoma, WHO grade II ependymal neoplasm, CD10, genetic, set, high frequency, Transforming Genes, atriopeptidase, CALLA, chromosome scaffold, disease management, Therapies, neutral endopeptidase 24.11, tumor, house mouse, associated, posterior end of organism, Ependymoma, Tumors, nuclear chromatin, Therapy, close to, Clear Cell Ependymoma, Age at Onset, suprasegmental structures, subdivided, gyltl1b-b, ribose nucleic acid, familial, ribonucleic acids, mouse, neoplastic disease, tumours, Anaplastic, Myxopapillary, shortened, MME, MDDGA6, fossae, mKIAA0609, Ribonukleinsaeure, Chemotherapy, Genetic Materials, pentosenucleic acids, Ribonucleic acids, KIAA0609, acetylglucosaminyltransferase-like 1A, Genetic Material, forked, fg, Acid, Mus musculus, YAP2, divided, gyltl1b, Pharmacotherapy, resistant, death rate, NFkB, mice, RELA, Encephalon, mdc1d, Swiss Mouse, depressions, common, INSDC_feature:gene, septate, Children, LARGE_HUMAN, Treatments, domesticus, Papillary, MDC1D, Oncogene, enr, Patient, Material, Proliferation, tanycytic ependymoma (histologic variant), Papillary Ependymomas, Cistron, inherited genetic, Mouse, rela-a, other neoplasm, short, accessory, Gruppe, the brain, Proliferating, EPN, cytoplasmic chromatin, supratentorial region, enkephalinase, chemotherapy, WHO grade II ependymal tumour, Neoplasms, peltate hair, number, Goal, Gene, pharmacotherapy, Pharmacotherapies, LARGE1, presence, supernumerary, froggy, Chemotherapies, NEOPL, Gyltl1a, House, p65, Gene Products, Mus musculus domesticus, neoplasm, Mice, Drug Therapies, Anaplastic Ependymomas, study, Genetic, Transforming Gene, Swiss, MDDGB6, proliferating, cerebrum, stubby, astrocytoma, Onset Age, tumour, papillary ependymoma (histologic variant), LARGE, subependymoma, concavity, Non-Polyadenylated RNA, BPFD#36, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), NFKB3, grupos, time of survival, Clients, ependymoma, Myxopapillary Ependymoma, Yki, YKI, NEP, constitutitional genetic, Anaplastic Ependymoma, Yorkie, Neoplastic Growth, COB1, RNA, grupo, clear cell ependymoma (histologic variant), RNS, Cistrons, encephalon, Client, Cell, group, near to, count in organism, neoplastic growth, survival, Discovery, Mus, yeast nucleic acid, xrela, skin fibroblast elastase, scales, SNQ3, WHO grade II ependymal tumor, glioblastoma multiforme, ribonucleic acid, Genes, groove, frequent, distinct, scale, ensemble, increased number, Non Polyadenylated RNA, Rest, Non-Polyadenylated, House Mice, patient, Ribonucleic Acid, AI325207, Age symptoms begin, disease of cellular proliferation, Laboratory Mice, Drug, present in greater numbers in organism, like-glycosyltransferase, Therapeutic, approaches, vicinity of, cardinality, Ependymomas, common acute lymphocytic leukemia antigen, Treatment, pharmacologic therapy, PAR1, endbrain, hereditary, depression, groupe, Laboratory Mouse, NEOPLASMS BENIGN, Neoplasia, V-rel reticuloendotheliosis viral oncogene homolog A (Avian), glycosyltransferase-like protein LARGE1falseena-DATASET-dkfz_b062-16-02-2018-17:18:40:151-347 - samplesThis dataset conatains RNA sequencing data from 24 patients. Up to two lanes per tumour sample have been seqeunced on a Illumina HiSeq2000 instrument in paired-end mode resulting in 58 Fastq files.2022-06-10 11:20:20EGAD00001003966960629258295EGAC00001000219EGAS00001002696