GENE-02. CHROMOSOME CONFORMATION ANALYSIS OF EPENDYMOMA IDENTIFIES PUTATIVE TUMOR DEPENDENCY GENES ACTIVATED BY DISTAL ONCOGENIC ENHANCERS. (23rd April 2019)

• Record Type: Journal Article
• Authors: Okonechnikov, Konstantin; Hübner, Jens-Martin; Kraft, Katerina; Hidalgo, Rocio Acuna; Bump, Rosalind; Chandran, Sahaana; Mundlos, Stefan; Mesirov, Jill; Pajtler, Kristian; Dixon, Jesse; Pfister, Stefan; Kool, Marcel; Chavez, Lukas
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii80
• Page End: ii81
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.073
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: By profiling enhancers in primary ependymoma tumors, we have recently identified putative oncogenes, molecular targets, and functional pathways. Inhibition of selected targets diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymoma. To associate enhancers with their likely target genes, we previously relied on linear proximity and co-activation analysis. While enhancers frequently regulate the nearest gene, unambiguous identification of enhancer target genes remains to be a challenge in the absence of chromosome conformation information. Consequently, we have now used HiC to map the 3-dimensional organization of tumor chromatin in the two most common and aggressive ependymoma subgroups: posterior fossa group A (PF-EPN-A) and supratentorial ependymomas with gene fusions involving the NF-κB subunit gene RELA (ST-EPN-RELA). By an integrative analysis of enhancer and gene expression in the context of the newly derived HiC data, we find that a large amount of the previously predicted enhancer target genes can be confirmed by physical interactions. Importantly, we also identify many new putative tumor-dependency genes activated by long-range promoter-enhancer interactions. These distal regulatory dependencies could not be predicted previously by proximity or gene-enhancer co-activation analysis alone due to marked differences in ependymoma chromosome conformation compared to normal human cell types. Complementary to the analysis of gene-enhancer interactions, we have also leveraged the HiC data for resolving structural rearrangements underlying copy number alterations frequently observed in PF-EPN-A tumors. Especially copy number gains of the 1q arm of chromosome 1 are associated with poor survival. Our preliminary results reveal complex structural variants that underlie 1q gains, which lead to inter-chromosomal rearrangements and affect several genes that potentially contribute to poor survival. We now aim to test the relevance of the novel candidate tumor-dependency genes for tumor cell growth and proliferation in-patient derived ependymoma models.