Acta Neuropathologica

, Volume 122, Issue 2, pp 231–240

Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

  • Paul A. Northcott
  • Thomas Hielscher
  • Adrian Dubuc
  • Stephen Mack
  • David Shih
  • Marc Remke
  • Hani Al-Halabi
  • Steffen Albrecht
  • Nada Jabado
  • Charles G. Eberhart
  • Wieslawa Grajkowska
  • William A. Weiss
  • Steven C. Clifford
  • Eric Bouffet
  • James T. Rutka
  • Andrey Korshunov
  • Stefan Pfister
  • Michael D. Taylor
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

Authors and Affiliations

  • Paul A. Northcott
    • 1
    • 2
  • Thomas Hielscher
    • 3
  • Adrian Dubuc
    • 1
    • 2
    • 4
  • Stephen Mack
    • 1
    • 2
    • 4
  • David Shih
    • 1
    • 2
    • 4
  • Marc Remke
    • 5
    • 6
  • Hani Al-Halabi
    • 7
  • Steffen Albrecht
    • 8
  • Nada Jabado
    • 9
  • Charles G. Eberhart
    • 10
  • Wieslawa Grajkowska
    • 11
  • William A. Weiss
    • 12
  • Steven C. Clifford
    • 13
  • Eric Bouffet
    • 14
  • James T. Rutka
    • 1
    • 4
    • 15
  • Andrey Korshunov
    • 16
  • Stefan Pfister
    • 5
    • 6
  • Michael D. Taylor
    • 1
    • 2
    • 4
    • 15
  1. 1.The Arthur and Sonia Labatt Brain Tumour Research CenterHospital for Sick ChildrenTorontoCanada
  2. 2.Program in Developmental and Stem Cell BiologyHospital for Sick ChildrenTorontoCanada
  3. 3.Division of BiostatisticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  5. 5.Division Molecular GeneticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of Pediatric Oncology, Hematology, ImmunologyUniversity of HeidelbergHeidelbergGermany
  7. 7.Department of Radiation OncologyMontreal General Hospital, McGill University Health CentreMontrealCanada
  8. 8.Department of PathologyMontreal Children’s Hospital, McGill University Health CentreMontrealCanada
  9. 9.Departments of Pediatrics and Human GeneticsMcGill University Health CentreMontrealCanada
  10. 10.Departments of Pathology, Ophthalmology and OncologyJohns Hopkins UniversityBaltimoreUSA
  11. 11.Department of PathologyChildren’s Memorial Health InstituteWarsawPoland
  12. 12.Departments of Neurology, Pediatrics, and Neurological SurgeryUCSFSan FranciscoUSA
  13. 13.Northern Institute for Cancer ResearchNewcastle UniversityNewcastleUK
  14. 14.Neuro-oncology Program, Division of Haematology/OncologyThe Hospital for Sick ChildrenTorontoCanada
  15. 15.Division of NeurosurgeryHospital for Sick ChildrenTorontoCanada
  16. 16.Clinical Cooperation Unit Neuropathology (G-380), German Cancer Research Center (DKFZ)HeidelbergGermany