Abstract
BackgroundNeuroblastoma (NB) tumors are well known for their pronounced clinical and molecular heterogeneity. The global gene expression and DNA copy number alterations have been shown to have profound differences in tumors of low or high stage and those with or without MYCN amplification. RNA splicing is an important regulatory mechanism of gene expression, and differential RNA splicing may be associated with the clinical behavior of a tumor.MethodsIn this study, we used exon array profiling to investigate global alternative splicing pattern of 47 neuroblastoma samples in stage 1 and stage 4 with normal or amplified MYCN copy number (stage 1-, 4- and 4+). The ratio of exon-level expression to gene-level expression was used to detect alternative splicing events, while the gene-level expression was applied to characterize whole gene expression change.ResultsPrincipal component analysis (PCA) demonstrated distinct splicing pattern in three groups of samples. Pairwise comparison identified genes with splicing changes and/or whole gene expression changes in high stage tumors. In stage 4- compared with stage 1- tumors, alternatively spliced candidate genes had little overlap with genes showing whole gene expression changes, 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. Those biological processes involved in stage 4- tumors were disrupted to a greater extent by both splicing and transcription regulations in stage 4+ tumors.ConclusionsOur results demonstrated a significant role of alternative splicing in high stage neuroblastoma, and suggested a MYCN-associated splicing regulation pathway in stage 4+ tumors. The identification of differentially spliced genes and pathways in neuroblastoma tumors of different stages and molecular subtypes may be important to the understanding of cancer biology and the discovery of diagnostic markers or therapeutic targets in neuroblastoma.
Highlights
Neuroblastoma (NB) tumors are well known for their pronounced clinical and molecular heterogeneity
Identification of alternatively spliced candidate genes To study the role of splicing regulation in high stage and MYCN amplified neuroblastoma, we used Human Exon 1.0 ST Array (HuEx) array to measure exon expression levels in 47 neuroblastoma samples from 10 stage 1, 28 stage 4, and 9 stage 4+ tumors (Table 1)
Alternative splicing events may be detected by normalized intensity (NI), which is defined as the ratio of exon-level probeset expression to gene-level transcript cluster expression [15]
Summary
Neuroblastoma (NB) tumors are well known for their pronounced clinical and molecular heterogeneity. Alternative splicing of pre-messenger RNA is nearly universal, involving more than 90% of human genes [1] It is an important regulatory mechanism of gene expression for tissue-specific functions. There have been numerous studies to identify tumor-specific splicing variants as diagnostic markers or therapeutic targets, only recently has alternative splicing in cancer been studied using genome-wide profiling methods [3,4,5,6,7]. MYCN is the most important biologic marker for neuroblastoma It is amplified in approximately 25% of de novo neuroblastoma cases and is more common in patients with advanced-stage disease. The goal was to identify stage- and MYCN amplification-specific splicing patterns in comparison to whole gene expression changes for the understanding of cancer biology and discovery of biomarkers or therapeutic targets in neuroblastoma
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