Acta Neuropathologica

, Volume 123, Issue 4, pp 485–499

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
Original Paper

DOI: 10.1007/s00401-012-0959-7

Cite this article as:
Dubuc, A.M., Morrissy, A.S., Kloosterhof, N.K. et al. Acta Neuropathol (2012) 123: 485. doi:10.1007/s00401-012-0959-7

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.

Keywords

MedulloblastomaAlternative splicingNeuronal developmentMolecular subgroupPediatric cancer

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Adrian M. Dubuc
    • 1
    • 2
    • 3
  • A. Sorana Morrissy
    • 1
    • 2
  • Nanne K. Kloosterhof
    • 4
    • 5
  • Paul A. Northcott
    • 1
    • 2
    • 3
  • Emily P. Y. Yu
    • 6
  • David Shih
    • 1
    • 2
    • 3
  • John Peacock
    • 1
    • 2
    • 3
  • Wieslawa Grajkowska
    • 7
  • Timothy van Meter
    • 8
  • Charles G. Eberhart
    • 9
  • Stefan Pfister
    • 10
  • Marco A. Marra
    • 11
  • William A. Weiss
    • 12
  • Stephen W. Scherer
    • 13
    • 14
  • James T. Rutka
    • 1
    • 3
  • Pim J. French
    • 4
  • Michael D. Taylor
    • 1
    • 2
    • 3
  1. 1.Division of NeurosurgeryArthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenTorontoCanada
  2. 2.Program in Developmental and Stem Cell BiologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  4. 4.Department of NeurologyErasmus MCRotterdamThe Netherlands
  5. 5.Department of Paediatric Oncology and HematologyErasmus MC, Sophia Children’s HospitalRotterdamThe Netherlands
  6. 6.Program in Biology and PharmacologyUniversity of Western OntarioLondonCanada
  7. 7.Department of PathologyChildren’s Memorial Health InstituteWarsawPoland
  8. 8.Department of NeurosurgeryMedical College of VirginiaRichmondUSA
  9. 9.Department of PathologyJohns Hopkins UniversityBaltimoreUSA
  10. 10.German Cancer Research CentreUniversity of HeidelbergHeidelbergGermany
  11. 11.British Columbia Cancer AgencyGenome Science CentreVancouverCanada
  12. 12.Helen Diller Family Comprehensive Cancer CentreUniversity of CaliforniaSan FranciscoUSA
  13. 13.The Centre for Applied GenomicsThe Hospital for Sick ChildrenTorontoCanada
  14. 14.Department of Molecular GeneticsUniversity of TorontoTorontoCanada