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Acta Neuropathol. 2012 Apr;123(4):485-499. doi: 10.1007/s00401-012-0959-7. Epub 2012 Feb 23.

Subgroup-specific alternative splicing in medulloblastoma.

Author information

1
Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
3
Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
4
Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
5
Department of Paediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.
6
Program in Biology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
7
Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
8
Department of Neurosurgery, Medical College of Virginia, Richmond, Virginia, USA.
9
Department of Pathology, Johns Hopkins Univertisy, Baltimore, Maryland, USA.
10
German Cancer Research Centre, University of Heidelberg, Heidelberg, Germany.
11
British Columbia Cancer Agency, Genome Science Centre, Vancouver, British Columbia, Canada.
12
Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, California, United States of America.
13
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
14
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
#
Contributed equally

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.

PMID:
22358458
PMCID:
PMC3984840
DOI:
10.1007/s00401-012-0959-7
[Indexed for MEDLINE]
Free PMC Article

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