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Subgroup-specific alternative splicing in medulloblastoma

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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.

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Authors and Affiliations

  1. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada

    Adrian M. Dubuc, A. Sorana Morrissy, Paul A. Northcott, David Shih, John Peacock, James T. Rutka & Michael D. Taylor

  2. Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Adrian M. Dubuc, A. Sorana Morrissy, Paul A. Northcott, David Shih, John Peacock & Michael D. Taylor

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Adrian M. Dubuc, Paul A. Northcott, David Shih, John Peacock, James T. Rutka & Michael D. Taylor

  4. Department of Neurology, Erasmus MC, Rotterdam, The Netherlands

    Nanne K. Kloosterhof & Pim J. French

  5. Department of Paediatric Oncology and Hematology, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands

    Nanne K. Kloosterhof

  6. Program in Biology and Pharmacology, University of Western Ontario, London, ON, Canada

    Emily P. Y. Yu

  7. Department of Pathology, Children’s Memorial Health Institute, Warsaw, Poland

    Wieslawa Grajkowska

  8. Department of Neurosurgery, Medical College of Virginia, Richmond, VA, USA

    Timothy van Meter

  9. Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

    Charles G. Eberhart

  10. German Cancer Research Centre, University of Heidelberg, Heidelberg, Germany

    Stefan Pfister

  11. British Columbia Cancer Agency, Genome Science Centre, Vancouver, BC, Canada

    Marco A. Marra

  12. Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, CA, USA

    William A. Weiss

  13. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada

    Stephen W. Scherer

  14. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Stephen W. Scherer

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  1. Adrian M. Dubuc
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Correspondence to Michael D. Taylor.

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A. M. Dubuc and A. S. Morrissy contributed equally to this work.

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Dubuc, A.M., Morrissy, A.S., Kloosterhof, N.K. et al. Subgroup-specific alternative splicing in medulloblastoma. Acta Neuropathol 123, 485–499 (2012). https://doi.org/10.1007/s00401-012-0959-7

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