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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)231-240
Number of pages10
JournalActa neuropathologica
Volume122
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • Genomics
  • Medulloblastoma
  • Molecular classification
  • Sonic hedgehog

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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