TY - JOUR
T1 - Molecular and Clinical Stratification of Astroblastomas
T2 - Three distinct Fusion-Defined Groups Informing Risk-Adapted Treatment Strategies
AU - Federico, Aniello
AU - Schmitt-Hoffner, Felix
AU - Fonseca, Adriana
AU - Geisemeyer, Neal
AU - Bruckner, Katharina
AU - Mauermann, Monika
AU - Sill, Martin
AU - Stichel, Damian
AU - Sturm, Dominik
AU - Schüller, Ulrich
AU - Tauziede-Espariat, Arnault
AU - Varlet, Pascale
AU - Capper, David
AU - Abdullaev, Zied
AU - Schrimpf, Daniel
AU - Selt, Florian
AU - Williamson, Lane
AU - Donson, Andrew M
AU - Antonelli, Manila
AU - Miele, Evelina
AU - Snuderl, Matija
AU - Brandner, Sebastian
AU - Łastowska, Maria
AU - Van Der Lugt, Jasper
AU - Bunt, Jens
AU - Kramm, Christof
AU - Kolenova, Alexandra
AU - Raghunathan, Aditya
AU - Wilson, Yelena
AU - Weintraub, Lauren
AU - Hansford, Jordan R
AU - Spiegl-Kreinecker, Sabine
AU - Aistleitner, Barbara
AU - Baroni, Lorena
AU - Zapotocky, Michal
AU - Ramaswamy, Vijay
AU - Korshunov, Andrey
AU - Jones, Barbara
AU - Kjaersgaard, Mimi
AU - Kranendonk, Mariëtte E
AU - Haberler, Christine
AU - Packer, Roger J
AU - Jäger, Natalie
AU - Deimling, Andreas Von
AU - Sahm, Felix
AU - Koster, Jan
AU - Aldape, Kenneth
AU - Pfister, Stefan M
AU - Hoff, Katja Von
AU - Gojo, Johannes
AU - Kool, Marcel
N1 - Publisher Copyright:
© The Author(s) 2025. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
PY - 2026/4
Y1 - 2026/4
N2 - 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 3 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 Groups A and C. Conclusions: Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the 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 tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.
AB - 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 3 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 Groups A and C. Conclusions: Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the 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 tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.
U2 - 10.1093/neuonc/noaf283
DO - 10.1093/neuonc/noaf283
M3 - Article
C2 - 41429568
SN - 1522-8517
VL - 28
SP - 1005
EP - 1019
JO - Neuro-oncology
JF - Neuro-oncology
IS - 4
ER -