title: Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct.
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.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Center, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Stephen
authors.initials: S
authors.lastname: Mack
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Hani
authors.initials: H
authors.lastname: Al-Halabi
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000328:Adult; D017668:Age of Onset; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D002648:Child; D016000:Cluster Analysis; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human