Subgroup-specific alternative splicing in medulloblastoma

Adrian M. Dubuc, A. Sorana Morrissy, Nanne K. Kloosterhof, Paul A. Northcott, Emily P.Y. Yu, David Shih, John Peacock, Wieslawa Grajkowska, Timothy Van Meter, Charles G. Eberhart, Stefan Pfister, Marco A. Marra, William A. Weiss, Stephen W. Scherer, James T. Rutka, Pim J. French, Michael D. Taylor

Research output: Contribution to journalArticle

Abstract

Medulloblastoma comprises four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P < 6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals overrepresentation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup-specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups.

Original languageEnglish (US)
Pages (from-to)485-499
Number of pages15
JournalActa neuropathologica
Volume123
Issue number4
DOIs
StatePublished - Apr 1 2012

Keywords

  • Alternative splicing
  • Medulloblastoma
  • Molecular subgroup
  • Neuronal development
  • Pediatric cancer

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Subgroup-specific alternative splicing in medulloblastoma'. Together they form a unique fingerprint.

  • Cite this

    Dubuc, A. M., Morrissy, A. S., Kloosterhof, N. K., Northcott, P. A., Yu, E. P. Y., Shih, D., Peacock, J., Grajkowska, W., Van Meter, T., Eberhart, C. G., Pfister, S., Marra, M. A., Weiss, W. A., Scherer, S. W., Rutka, J. T., French, P. J., & Taylor, M. D. (2012). Subgroup-specific alternative splicing in medulloblastoma. Acta neuropathologica, 123(4), 485-499. https://doi.org/10.1007/s00401-012-0959-7