Journal Article

PROGNOSTIC SIGNIFICANCE OF CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR CHARACTERISTICS OF MEDULLOBLASTOMAS IN THE PROSPECTIVE HIT2000 MULTICENTER CLINICAL TRIAL COHORT

Torsten Pietsch, Rene Schmidt, Marc Remke, Andrey Korshunov, Volker Hovestadt, David TW Jones, Jörg Felsberg, Kerstin Kaulich, Tobias Goschzik, Marcel Kool, Paul A. Northcott, Katja von Hoff, André O. von Bueren, Carsten Friedrich, Heyko Skladny, Gudrun Fleischhack, Michael D. Taylor, Friedrich Cremer, Peter Lichter, Andreas Faldum, Guido Reifenberger, Stefan Rutkowski and Stefan M. Pfister

in Neuro-Oncology

Volume 16, issue suppl_3, pages iii24-iii25
Published in print July 2014 | ISSN: 1522-8517
Published online July 2014 | e-ISSN: 1523-5866 | DOI: http://dx.doi.org/10.1093/neuonc/nou208.7
PROGNOSTIC SIGNIFICANCE OF CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR CHARACTERISTICS OF MEDULLOBLASTOMAS IN THE PROSPECTIVE HIT2000 MULTICENTER CLINICAL TRIAL COHORT

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BACKGROUND: This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. METHODS: Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a validation (n = 57) dataset. All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. RESULTS: By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, TOP2A copy-number, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining “intermediate molecular risk” population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified and validated, with speckled synaptophysin expression indicating worse outcome. CONCLUSIONS: Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk-stratification of medulloblastoma. A simple clinico-pathological risk score for “intermediate molecular risk” patients was identified, which deserves further validation. SECONDARY CATEGORY: Pediatrics.

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Subjects: Medical Oncology ; Neurology

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