Original Paper

Acta Neuropathologica

, Volume 122, Issue 2, pp 231-240

Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

  • Paul A. NorthcottAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenProgram in Developmental and Stem Cell Biology, Hospital for Sick Children
  • , Thomas HielscherAffiliated withDivision of Biostatistics, German Cancer Research Center (DKFZ)
  • , Adrian DubucAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenProgram in Developmental and Stem Cell Biology, Hospital for Sick ChildrenDepartment of Laboratory Medicine and Pathobiology, University of Toronto
  • , Stephen MackAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenProgram in Developmental and Stem Cell Biology, Hospital for Sick ChildrenDepartment of Laboratory Medicine and Pathobiology, University of Toronto
  • , David ShihAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenProgram in Developmental and Stem Cell Biology, Hospital for Sick ChildrenDepartment of Laboratory Medicine and Pathobiology, University of Toronto
  • , Marc RemkeAffiliated withDivision Molecular Genetics, German Cancer Research Center (DKFZ)Department of Pediatric Oncology, Hematology, Immunology, University of Heidelberg
  • , Hani Al-HalabiAffiliated withDepartment of Radiation Oncology, Montreal General Hospital, McGill University Health Centre
  • , Steffen AlbrechtAffiliated withDepartment of Pathology, Montreal Children’s Hospital, McGill University Health Centre
  • , Nada JabadoAffiliated withDepartments of Pediatrics and Human Genetics, McGill University Health Centre
    • , Charles G. EberhartAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenDepartments of Pathology, Ophthalmology and Oncology, Johns Hopkins University
    • , Wieslawa GrajkowskaAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenDepartment of Pathology, Children’s Memorial Health Institute
    • , William A. WeissAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenDepartments of Neurology, Pediatrics, and Neurological Surgery, UCSF
    • , Steven C. CliffordAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenNorthern Institute for Cancer Research, Newcastle University
    • , Eric BouffetAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenNeuro-oncology Program, Division of Haematology/Oncology, The Hospital for Sick Children
    • , James T. RutkaAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenDepartment of Laboratory Medicine and Pathobiology, University of TorontoDivision of Neurosurgery, Hospital for Sick Children
    • , Andrey KorshunovAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenClinical Cooperation Unit Neuropathology (G-380), German Cancer Research Center (DKFZ)
    • , Stefan PfisterAffiliated withDivision Molecular Genetics, German Cancer Research Center (DKFZ)Department of Pediatric Oncology, Hematology, Immunology, University of Heidelberg
    • , Michael D. TaylorAffiliated withThe Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick ChildrenProgram in Developmental and Stem Cell Biology, Hospital for Sick ChildrenDepartment of Laboratory Medicine and Pathobiology, University of TorontoDivision of Neurosurgery, Hospital for Sick Children Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

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

Medulloblastoma Sonic hedgehog Molecular classification Genomics