Transcriptomic Analysis Revealed an Emerging Role of Alternative Splicing in Embryonal Tumor with Multilayered Rosettes.

Dina Hesham,Shahenda El-Naggar

doi:10.3390/genes11091108

Abstract

Embryonal tumor with multilayered rosettes (ETMR) is an aggressive and rare pediatric embryonal brain tumor. Amplification of C19MC microRNA cluster and expression of 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 has not been thoroughly investigated. In the current study, a comprehensive analysis was performed on published unprocessed RNA-seq reads of tissue-matched ETMR and fetal controls datasets. Gene expression was quantified in samples using Kallisto/sleuth pipeline. For the alternative splicing analysis, STAR, SplAdder and rMATS were used. Functional enrichment analysis was subsequently performed using Metascape. The expression analysis identified a total of 3622 differentially expressed genes (DEGs) between ETMR and fetal controls while 1627 genes showed differential alternative splicing patterns. Interestingly, genes with significant alternative splicing events in ETMR were identified to be involved in signaling pathways such as ErbB, mTOR and MAPK pathways as well as ubiquitin-mediated proteolysis, cell cycle and autophagy. Moreover, up-regulated DEGs with alternative splicing events were involved in important biological processes including nuclear transport, regulation of cell cycle and regulation of Wnt signaling pathway. These findings highlight the role of aberrant alternative splicing in shaping the ETMR tumor landscape, and the identified pathways constitute potential therapeutic targets.

Highlights

Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive pediatric embryonal brain tumor affecting infants and young children less than 4 years of age [1,2].Despite intensive multimodal treatment, ETMR is a disease of poor prognosis with only 20% long-term survival [3,4,5,6,7,8,9]
Genes with significant alternative splicing events in ETMR were identified to be involved in signaling pathways such as ErbB, mTOR and MAPK pathways as well as ubiquitin-mediated proteolysis, cell cycle and autophagy
Up-regulated differentially expressed genes (DEGs) with alternative splicing events were involved in important biological processes including nuclear transport, regulation of cell cycle and regulation of Wnt signaling pathway

Summary

Introduction

ETMR is a disease of poor prognosis with only 20% long-term survival [3,4,5,6,7,8,9]. ETMRs are mostly characterized by two distinctive molecular markers; amplification of. 3 β (DNMT3B) was observed in ETMR [11]. High expression of LIN28A is implicated in neural development and pathogenesis of other advanced cancers [12]. The role of LIN28A in regulating splicing and gene expression programs has been investigated in cancer. LIN28A was reported to cause significant isoform switches in genes involved in breast cancer biology [13]

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Conclusion