Molecular biology of medulloblastoma: bridging the gap between research and practice

Abstract

Medulloblastoma, the most common primary pediatric malignant brain tumor, is a molecularly heterogeneous disease with different developmental origins, distinct phenotypes, diverse biological behavior and contrasting clinical outcomes. The current clinico-radiological risk classification fails to take account of this heterogeneity and resultant prognostic variability. It is widely accepted that dysregulation of normal developmental processes constitutes a key mechanism of tumorigenesis in at least a subset of medulloblastomas. Several attempts at biological classification have successfully identified distinct subgroups with subgroup-specific gene signatures, demographics, histologic subtypes and metastases; among these, tumors involving the wingless and sonic hedgehog signaling pathways have been the most reliably and consistently identified. However, such integrative genomic approaches have limited applicability in the clinic owing to the need for fresh frozen tissues and elaborate molecular biology tools. A novel four-antibody approach to subgroup medulloblastoma using immunohistochemistry on archival specimens as proposed by Northcott et al. appears extremely promising as it can be applied in any basic neuropathology laboratory across the globe. There is a compelling need to integrate assays of molecular biomarkers performed on archival specimens into stratification schemes for medulloblastoma alongside clinical and pathologic outcome indicators to refine risk stratification for individualizing therapy.