title: Subgroup-specific alternative splicing in medulloblastoma.
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.
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: A Sorana
authors.initials: AS
authors.lastname: Morrissy
authors.affiliation: Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.|Department of Paediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.
authors.forename: Nanne K
authors.initials: NK
authors.lastname: Kloosterhof
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: Program in Biology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Emily Py
authors.initials: EP
authors.lastname: Yu
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Peacock
authors.affiliation: Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.affiliation: Department of Neurosurgery, Medical College of Virginia, Richmond, Virginia, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: van Meter
authors.affiliation: Department of Pathology, Johns Hopkins Univertisy, Baltimore, Maryland, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.affiliation: German Cancer Research Centre, University of Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.affiliation: British Columbia Cancer Agency, Genome Science Centre, Vancouver, British Columbia, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Helen Diller Family Comprehensive Cancer Centre, University of California, San Francisco, California, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.affiliation: Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
authors.affiliation: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.|Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000145:classification* / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology; D005333:Fetus; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000235:genetics; D008527:Medulloblastoma / Q000145:classification* / Q000235:genetics*; D046228:Microarray Analysis; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D015203:Reproducibility of Results; D051153:Wnt Proteins / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; C496946:KCNA1 protein, human; C509239:SHH protein, human; D051153:Wnt Proteins; D051662:Kv1.1 Potassium Channel; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C