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Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

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Abstract

Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.

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Authors and Affiliations

  1. The Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick Children, Toronto, ON, Canada

    Paul A. Northcott, Adrian Dubuc, Stephen Mack, David Shih, James T. Rutka & Michael D. Taylor

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

    Paul A. Northcott, Adrian Dubuc, Stephen Mack, David Shih & Michael D. Taylor

  3. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Thomas Hielscher

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

    Adrian Dubuc, Stephen Mack, David Shih, James T. Rutka & Michael D. Taylor

  5. Division Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Marc Remke & Stefan Pfister

  6. Department of Pediatric Oncology, Hematology, Immunology, University of Heidelberg, Heidelberg, Germany

    Marc Remke & Stefan Pfister

  7. Department of Radiation Oncology, Montreal General Hospital, McGill University Health Centre, Montreal, QC, Canada

    Hani Al-Halabi

  8. Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada

    Steffen Albrecht

  9. Departments of Pediatrics and Human Genetics, McGill University Health Centre, Montreal, QC, Canada

    Nada Jabado

  10. Departments of Pathology, Ophthalmology and Oncology, Johns Hopkins University, Baltimore, MD, USA

    Charles G. Eberhart

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

    Wieslawa Grajkowska

  12. Departments of Neurology, Pediatrics, and Neurological Surgery, UCSF, San Francisco, CA, USA

    William A. Weiss

  13. Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

    Steven C. Clifford

  14. Neuro-oncology Program, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada

    Eric Bouffet

  15. Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada

    James T. Rutka & Michael D. Taylor

  16. Clinical Cooperation Unit Neuropathology (G-380), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Andrey Korshunov

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  1. Paul A. Northcott
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  2. Thomas Hielscher
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Correspondence to Michael D. Taylor.

Electronic supplementary material

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401_2011_846_MOESM1_ESM.pdf

Supplementary Fig. 1. Pediatric and adult Shh-medulloblastomas exhibit distinct cytogenetic profiles. (a) Genome-wide DNA copy number profiles for pediatric and adult Shh-medulloblastomas. Copy number was determined using either 100 K or 500 K SNP array platforms and data visualized using the Integrative Genomics Viewer (IGV). (b, c) Pediatric Shh-medulloblastomas appear to exhibit more frequent gains of chromosome 2 (b) and loss of chromosome 10 (c). (d) Representative FISH showing MYCN amplification in pediatric and adult Shh-medulloblastomas. (PDF 116 kb)

401_2011_846_MOESM2_ESM.pdf

Supplementary Fig. 2. Prognostic significance of cytogenetic aberrations in Shh-medulloblastoma. (a-c) OS and PFS for Shh-medulloblastomas based on chromosome 2 gain (a), 17p deletion (b), and 17q gain (c). (PDF 46 kb)

Supplementary material 3 (XLSX 123 kb)

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Northcott, P.A., Hielscher, T., Dubuc, A. et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol 122, 231–240 (2011). https://doi.org/10.1007/s00401-011-0846-7

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  • DOI: https://doi.org/10.1007/s00401-011-0846-7

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