Molecular and Clinical Stratification of Astroblastomas: Three Distinct Fusion-Defined Groups Informing Risk-Adapted Treatment Strategies
Background:Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined.
Methods: We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as “Astroblastoma, MN1-altered” under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses.
Results: DNA methylation analyses identified three groups: Group A (n=143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n=37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n=20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Group A and C.
Conclusions: Astroblastoma, MN1-altered, comprises three molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including identification of potential predictive biomarkers like 14q/16q loss, provide a framework for development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse entity, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.