Abstract 1430: Characterization of the medulloblastoma splice-ome reveals subgroup-specific changes in alternative splicing and isoform expression patterns

Abstract

Abstract Medulloblastoma candidate gene approaches have previously identified alternative splicing and isoform expression changes affecting genes critical for cerebellar development and medulloblastoma pathogenesis. Here we present a bioinformatic characterization of the medulloblastoma splice-ome in 103 primary tumors and 14 normal cerebella samples. Medulloblastomas display a statistically significant increase in alternative splicing relative to normal fetal cerebella (2.3-times; P<6.47E-8), with splicing patterns that are specific to each molecular subgroup. Unsupervised hierarchical clustering of alternatively spliced genes accurately assigns medulloblastomas to their correct subgroup. One-third of all medulloblastomas (n=26) display a ‘hyper-spliced’ phenotype, with median splicing levels four-times greater than non-hyperspliced tumors. Hyperspliced medulloblastomas show a relatively worse overall survival (P<3.08E-2), and are seen across all molecular subgroups. Our analysis identifies previously reported splicing events targeting ERBB4 (mixed MB), GLI1 (SHH) and PTCH1 (SHH), supporting our approach. Subgroup-specific pathway analysis of alternatively spliced genes reveals extensive deregulation of neuronal pathways in non-WNT medulloblastomas, with the specific targeting of genes important for axonal guidance, synaptic transmission and neuronal differentiation. Finally, we present evidence for putative regulation of alternative splicing by antisense transcription. These data further demonstrate the differences between medulloblastoma subgroups, and highlight alternative splicing and isoform expression as a mechanism contributing to the transcriptional heterogeneity between subgroups, and perhaps to subgroup specific pathogenic mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1430. doi:1538-7445.AM2012-1430