Molecular and clinical stratification of astroblastomas: Three distinct fusion-defined groups informing risk-adapted treatment strategies.
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Federico Aniello, Schmitt-Hoffner Felix, Fonseca Adriana, Geisemeyer Neal, Bruckner Katharina, Mauermann Monika, Sill Martin, Stichel Damian, Sturm Dominik, Schüller Ulrich, Tauziede-Espariat Arnault, Varlet Pascale, Capper David, Abdullaev Zied, Schrimpf Daniel, Selt Florian, Williamson Lane, Donson Andrew M, Antonelli Manila, Miele Evelina, Snuderl Matija, Brandner Sebastian, Łastowska Maria, van der Lugt Jasper, Bunt Jens, Kramm Christof, Kolenova Alexandra, Raghunathan Aditya, Wilson Yelena, Weintraub Lauren, Hansford Jordan R, Spiegl-Kreinecker Sabine, Aistleitner Barbara, Baroni Lorena, Zapotocky Michal, Ramaswamy Vijay, Korshunov Andrey, Jones Barbara, Kjaersgaard Mimi, Kranendonk Mariëtte E, Haberler Christine, Packer Roger J, Jäger Natalie, von Deimling Andreas, Sahm Felix, Koster Jan, Aldape Kenneth, Pfister Stefan M, von Hoff Katja, Gojo Johannes, Kool Marcel
Аннотация
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.