RNA splicing is an important regulatory mechanism of gene expression providing various functions for specific cells including cancers. In this study, we investigated global alternative splicing pattern in neuroblastoma using Affymetrix exon array (HuEx) and deep sequencing approach (RNA-Seq). Exon array profiling was performed on 47 neuroblastoma samples in stage 1 and stage 4 with normal or amplified MYCN copy number (stage 1-, 4- and 4+). Principal component analysis demonstrated distinct splicing pattern in three groups of samples. In stage 4- compared with stage 1- tumors, differentially spliced candidate genes (n=355) had little overlap with genes showing whole gene expression changes (n=158), and most of them were involved in different biological processes. In contrast, a larger number of genes exhibited either exon-level splicing, gene-level expression, or both changes in stage 4+ versus stage 1- tumors. To validate exon array results, we performed transcriptome sequencing of selected samples with stage 1-, 4-, or 4+ neuroblastomas. The concept of splicing index was adapted to measure RNA splicing by short sequence reads. Both exon array and deep sequencing data demonstrated differential splicing of microtubule-associated genes, which may play an important role in enhanced genomic instabilities and tumor development. In conclusion, our results demonstrated a significant contribution of alternative or aberrant splicing to neuroblastoma development. The identification of differentially spliced genes and pathways in high risk neuroblastomas may be essential to the understanding of cancer biology and the discovery of diagnostic biomarkers or therapeutic targets in neuroblastoma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2225.