Abstract LB-220: Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes

Abstract

Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare variant of embryonal brain tumors. Amplification of C19MC microRNA cluster and expression LIN28 are distinctive features of ETMR. Despite the increasing efforts to decipher ETMR, the biology remains poorly understood. To date, the role of aberrant alternative splicing in ETMR is not thoroughly investigated. In the current study a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue- matched ETMR (SRP032476), and fetal controls from the Human Developmental Biology Resource (HDBR) (E-MTAB-4840) datasets. Gene expression was quantified in samples using kallisto/sleuth pipeline. For the alternative splicing analysis, reads were mapped to the genome (hg38) using STAR. Identification and quantification of alternative splicing events (skipped exon, alternative 5′ and 3′splice sites, mutually exclusive exons, multi Exons Skip and retained intron) were carried out using SplAdder. Functional enrichment analysis for the differentially expressed and the differentially spliced genes was subsequently performed using Metascape. All statistical values reported were corrected for multiple hypothesis testing by Benjamini-Hochberg false discovery rate (q-values).The expression analysis revealed a total of 2205 differentially expressed genes (DEGs) between ETMR and fetal controls while 2446 showed differential alternative splicing patterns. DEGs with significant alternative splicing events were identified to be involved in ubiquitin mediated proteolysis, endocytosis, RNA transport, regulation of actin cytoskeleton pathways as well as histone modification. Interestingly, DEGs with intron retention events were involved in various signaling pathways including TGF-beta signaling pathway, MAPK signaling pathway and ErbB signaling pathway. These findings highlight the role of defective alternative splicing in shaping ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets. Citation Format: Dina Hesham AbouRaya, Shahenda El-Naggar. Functional consequences of aberrant alternative splicing in embryonal tumor with multilayered rosettes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-220.