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Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

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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.

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Correspondence to Michael D. Taylor.

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401_2011_846_MOESM1_ESM.pdf

Supplementary Fig. 1. Pediatric and adult Shh-medulloblastomas exhibit distinct cytogenetic profiles. (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

Supplementary Fig. 2. Prognostic significance of cytogenetic aberrations in Shh-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)

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Northcott, P.A., Hielscher, T., Dubuc, A. et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol 122, 231–240 (2011). https://doi.org/10.1007/s00401-011-0846-7

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  • DOI: https://doi.org/10.1007/s00401-011-0846-7

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