Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

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 Shhmedulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shhmedulloblastomas, 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 Electronic supplementary material The online version of this article (doi:10.1007/s00401-011-0846-7) contains supplementary material, which is available to authorized users. P. A. Northcott  A. Dubuc  S. Mack  D. Shih  J. T. Rutka  M. D. Taylor (&) The Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick Children, Toronto, ON, Canada e-mail: mdtaylor@sickkids.ca P. A. Northcott  A. Dubuc  S. Mack  D. Shih  M. D. Taylor Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada T. Hielscher Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany A. Dubuc  S. Mack  D. Shih  J. T. Rutka  M. D. Taylor Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M. Remke  S. Pfister Division Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany M. Remke  S. Pfister Department of Pediatric Oncology, Hematology, Immunology, University of Heidelberg, Heidelberg, Germany H. Al-Halabi Department of Radiation Oncology, Montreal General Hospital, McGill University Health Centre, Montreal, QC, Canada S. Albrecht Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada N. Jabado Departments of Pediatrics and Human Genetics, McGill University Health Centre, Montreal, QC, Canada C. G. Eberhart Departments of Pathology, Ophthalmology and Oncology, Johns Hopkins University, Baltimore, MD, USA W. Grajkowska Department of Pathology, Children’s Memorial Health Institute, Warsaw, Poland W. A. Weiss Departments of Neurology, Pediatrics, and Neurological Surgery, UCSF, San Francisco, CA, USA S. C. Clifford Northern Institute for Cancer Research, Newcastle University, Newcastle, UK E. Bouffet Neuro-oncology Program, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada 123 Acta Neuropathol (2011) 122:231–240 DOI 10.1007/s00401-011-0846-7 Shh-medulloblastomas. Children with desmoplastic Shhmedulloblastomas 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 Shhmedulloblastomas (n = 151) revealed significant overrepresentation 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.