Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct

• Published in: Acta neuropathologica Vol. 122; no. 2; pp. 231 - 240
• Main Authors: Northcott, Paul A., Hielscher, Thomas, Dubuc, Adrian, Mack, Stephen, Shih, David, Remke, Marc, Al-Halabi, Hani, Albrecht, Steffen, Jabado, Nada, Eberhart, Charles G., Grajkowska, Wieslawa, Weiss, William A., Clifford, Steven C., Bouffet, Eric, Rutka, James T., Korshunov, Andrey, Pfister, Stefan, Taylor, Michael D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2011; Springer Nature B.V
• Subjects: Adult; Adults; Age; Age of Onset; Cancer research; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - pathology; Child; Cluster Analysis; Datasets; Female; Gene expression; Genomics; Hedgehog Proteins - genetics; Histology; Humans; Infant; Male; Medical prognosis; Medical research; Medicine; Medicine & Public Health; Medulloblastoma - genetics; Medulloblastoma - pathology; Metastasis; Mutation; Neurosciences; Oncology; Original Paper; Pathology; Pediatrics; Research centers; Tumors; Canada; Montreal Quebec Canada; United States > US; Germany; Molecular classification; Sonic hedgehog; Medulloblastoma; Genomics
• ISSN: 0001-6322; 1432-0533; 1432-0533
• DOI: 10.1007/s00401-011-0846-7

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.