Abstract
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.
Highlights
Medulloblastoma, the most frequent embryonal brain tumor in children, comprises four subgroups (WNT, SHH, Group 3, Group 4) with distinct cellular origin, histopathological characteristics, pathogenetic events, demographical features, localization within the posterior fossa, and clinical behavior [1, 16, 17, 21, 26, 31, 32]
With the present study including subgrouping, Fluorescence in situ hybridization (FISH) or Multiplex ligation‐dependent probe amplification (MLPA) to detect monosomy 6, and Sanger sequencing of CTNNB1, we aim to provide a rationale as to which of these markers should best be applied in a clinical study setting
Histopathological classification according to the current WHO classification, chromosome 17p, and 10q status were found to be prognostic of overall survival (OS)
Summary
Medulloblastoma, the most frequent embryonal brain tumor in children, comprises four subgroups (WNT, SHH, Group 3, Group 4) with distinct cellular origin, histopathological characteristics, pathogenetic events, demographical features, localization within the posterior fossa, and clinical behavior [1, 16, 17, 21, 26, 31, 32]. Current treatment stratification is based on patient age, M-stage, extent of initial surgery, and histopathological subtyping. The majority of infants (
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