Acta Neuropathologica

, Volume 122, Issue 2, pp 231–240

Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

Authors

  • Paul A. Northcott
    • The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick Children
    • Program in Developmental and Stem Cell BiologyHospital for Sick Children
  • Thomas Hielscher
    • Division of BiostatisticsGerman Cancer Research Center (DKFZ)
  • Adrian Dubuc
    • The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick Children
    • Program in Developmental and Stem Cell BiologyHospital for Sick Children
    • Department of Laboratory Medicine and PathobiologyUniversity of Toronto
  • Stephen Mack
    • The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick Children
    • Program in Developmental and Stem Cell BiologyHospital for Sick Children
    • Department of Laboratory Medicine and PathobiologyUniversity of Toronto
  • David Shih
    • The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick Children
    • Program in Developmental and Stem Cell BiologyHospital for Sick Children
    • Department of Laboratory Medicine and PathobiologyUniversity of Toronto
  • Marc Remke
    • Division Molecular GeneticsGerman Cancer Research Center (DKFZ)
    • Department of Pediatric Oncology, Hematology, ImmunologyUniversity of Heidelberg
  • Hani Al-Halabi
    • Department of Radiation OncologyMontreal General Hospital, McGill University Health Centre
  • Steffen Albrecht
    • Department of PathologyMontreal Children’s Hospital, McGill University Health Centre
  • Nada Jabado
    • Departments of Pediatrics and Human GeneticsMcGill University Health Centre
  • Charles G. Eberhart
    • Departments of Pathology, Ophthalmology and OncologyJohns Hopkins University
  • Wieslawa Grajkowska
    • Department of PathologyChildren’s Memorial Health Institute
  • William A. Weiss
    • Departments of Neurology, Pediatrics, and Neurological SurgeryUCSF
  • Steven C. Clifford
    • Northern Institute for Cancer ResearchNewcastle University
  • Eric Bouffet
    • Neuro-oncology Program, Division of Haematology/OncologyThe Hospital for Sick Children
  • James T. Rutka
    • The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick Children
    • Department of Laboratory Medicine and PathobiologyUniversity of Toronto
    • Division of NeurosurgeryHospital for Sick Children
  • Andrey Korshunov
    • Clinical Cooperation Unit Neuropathology (G-380), German Cancer Research Center (DKFZ)
  • Stefan Pfister
    • Division Molecular GeneticsGerman Cancer Research Center (DKFZ)
    • Department of Pediatric Oncology, Hematology, ImmunologyUniversity of Heidelberg
    • The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick Children
    • Program in Developmental and Stem Cell BiologyHospital for Sick Children
    • Department of Laboratory Medicine and PathobiologyUniversity of Toronto
    • Division of NeurosurgeryHospital for Sick Children
Original Paper

DOI: 10.1007/s00401-011-0846-7

Cite this article as:
Northcott, P.A., Hielscher, T., Dubuc, A. et al. Acta Neuropathol (2011) 122: 231. doi:10.1007/s00401-011-0846-7

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.

Keywords

MedulloblastomaSonic hedgehogMolecular classificationGenomics

Supplementary material

401_2011_846_MOESM1_ESM.pdf (117 kb)
SupplementaryFig.1.PediatricandadultShh-medulloblastomasexhibitdistinctcytogeneticprofiles. (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 (46 kb)
SupplementaryFig.2.PrognosticsignificanceofcytogeneticaberrationsinShh-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)
401_2011_846_MOESM3_ESM.xlsx (124 kb)
Supplementary material 3 (XLSX 123 kb)

Copyright information

© Springer-Verlag 2011