MDB-84. IDENTIFICATION AND CHARACTERIZATION OF NOVEL TRANSCRIBED ULTRA-CONSERVED REGIONS AS LONG NON-CODING RNAS IN MEDULLOBLASTOMA

Abstract

Abstract BACKGROUND Medulloblastoma is the most common malignant pediatric brain tumor. While medulloblastoma survival has improved with molecular subgrouping, children who undergo standard of care treatments frequently experience permanent neurological deficits and many still face poor prognoses. This work investigates the role of “Transcribed Ultra-Conserved Regions” (TUCRs) in medulloblastoma about which there is no published literature. TUCRs represent a distinct group of 481 putative lncRNAs that are 100% conserved across human, mouse, and rat genomes. These elements change 20 times slower than the average genomic region and are therefore under intense negative selection. Since their discovery, TUCRs have remained exceedingly underexamined within cancer research. We hypothesize that TUCRs play critical roles in the molecular basis of medulloblastoma which will lead to the development of targeted therapies for medulloblastoma of which there are none approved. METHODS We used RNA-sequencing and differential gene expression analysis of medulloblastoma tumors as compared to normal cerebellum samples to investigate TUCR dysregulation followed by Kaplan-Meier correlation to survival analysis. We generated a multifaceted scoring and prioritization system to rank TUCRs in medulloblastoma. Top ranked TUCRs were then investigated using in vitro functional experimentation in medulloblastoma cell lines. RESULTS Bioinformatics analysis of medulloblastoma tumors revealed significant TUCR dysregulation and identified numerous TUCRs whose expression correlated with overall survival. Application of the computational scoring system determined the top ten intergenic TUCRs in medulloblastoma. Analysis of medulloblastoma cell lines indicated significant dysregulation of these TUCRs and functional assays showed that uc.403 promoted cell proliferation. CONCLUSIONS We are continuing to investigate the functional effects and mechanisms of action of these select intergenic TUCRs in medulloblastoma. Altogether, our work investigates the oncogenic and tumor suppressive nature of TUCRs. It represents the first study of TUCRs in medulloblastoma that will significantly advance our basic understanding of this highly understudied class of molecules.