DIPG-43. CLINICAL AND MOLECULAR CHARACTERISTIC OF A NEW SUBTYPE OF DMG, H3K27-ALTERED WITH MAPK-ACTIVATING CO-DRIVER MUTATIONS - Archive ouverte HAL Accéder directement au contenu
Communication Dans Un Congrès Année : 2023

DIPG-43. CLINICAL AND MOLECULAR CHARACTERISTIC OF A NEW SUBTYPE OF DMG, H3K27-ALTERED WITH MAPK-ACTIVATING CO-DRIVER MUTATIONS

Lucie Auffret
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Thomas Kergrohen
Medhi Touat
Marie-Anne Debily
David Castel

Résumé

Diffuse midline gliomas (DMG) represent a big challenge in neuro-oncology. These tumors occur more frequently in children and are presently incurable. They are characterized by a K27M substitution in H3.1 or H3.3 histone tail or the overexpression of EZHIP (EZH Inhibitory Protein). These three alterations induce a global loss of trimethylation in H3K27 with a specific epigenic and transcriptomic remodeling. The additional oncogenic events and the clinical behavior are also distinct according to the driver event. Based on these differences, the H3K27-altered DMG is now classified in 4 subtypes by the latest edition of the WHO Classification of CNS tumors. Even with this new subclassification, the H3.3K27M subgroup still appears heterogenous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tend to have a better prognosis. To better study the role of these co-driver alterations that activate the mitogen activated protein kinase (MAPK) signaling, we assembled a large pediatric and adult cohort of H3K27-altered DMG comprising 25 new DMG patients mutated in FGFR1 or BRAFV600E and 37 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylome analysis on this extended cohort. Interestingly, the results show clear differences with other DMG subtypes, including: specific DNA methylation profile, senescence signature, better overall survival (median around 3 years), older age at diagnosis, specific histological and radiological presentations with calcifications or more circumscribed tumors. Additionally, in specific cases, we show that the MAPK-activating mutation occurred subsequently to the histone H3K27M mutation. In conclusion, DMG, H3K27-altered harboring MAPK activating mutations represent a new subtype of DMG also frequent in adults, and deserve further attention with respect to specific therapeutic challenges.
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Dates et versions

hal-04416061 , version 1 (25-01-2024)

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Lucie Auffret, Yassine Ajlil, Thomas Kergrohen, Arnault Tauziède-Espariat, Chloe Puiseux, et al.. DIPG-43. CLINICAL AND MOLECULAR CHARACTERISTIC OF A NEW SUBTYPE OF DMG, H3K27-ALTERED WITH MAPK-ACTIVATING CO-DRIVER MUTATIONS. 2023 Pediatric Neuro-Oncology Research Conference, Jun 2023, Washington, United States. pp.i22-i23, ⟨10.1093/neuonc/noad073.090⟩. ⟨hal-04416061⟩
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