Path-37. a New Subtype of Diffuse Midline Glioma, H3 K27 and Braf/fgfr1 Co-altered, Exhibits Specific Biological Characteristics and New Therapeutic Vulnerabilities
Year: 2024
Type: conference-abstract
Abstract: Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumor type is classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System tumors. However, we recently identified a new subtype of DMG by assembling a retrospective cohort of 60 adult and pediatric DMG cases harboring BRAF or FGFR1 mutations in addition to the H3K27M mutation or EZHIP overexpression. Comprehensive clinical, histological, radiological, and genomic, analyses allowed to identify distinct genotype-phenotype characteristics. Contrary to other DMG, these tumors occur more frequently in the thalamus (27% vs. 70% for BRAFV600E or 58% for FGFR1MUT), and in adults in the case of FGFRMUT tumors. Importantly, these patients display a longer overall survival with a median above three years. Unsupervised analysis of DNA methylation profiles regrouped these MAPK-altered DMG in a methylation cluster distinct from other DMG H3K27, but also lower-grade midline tumors driven by FGFR1 or BRAF mutations Additionally, this new DMG subtype harbors atypical radiological and histopathological profiles with calcification and/or a solid tumor component both for BRAFV600E and FGFR1MUT cases that can suggest this differential diagnosis. Further analyses of the transcriptome of these tumors compared to canonical DMG H3K27-altered showed an expression signature of senescence with activation of a TP53/CDKN1A axis, together with a strong upregulation of the PI3K/AKT/MTOR pathway. Our current modelling of the drug response using patient-derived models of these specific DMG will permit to rapidly prioritize treatment strategies. Additionally, our clinical experience in treating these patients suggests a higher response to everolimus and imipridone ONC201 in this specific subtype. In conclusion, DMG H3 K27 and BRAF/FGFR1 co-altered, represent a new subtype of DMG with distinct specific characteristics compared to canonical DMG H3K27 and data accumulated strongly support their separate stratification in clinical trials and specific therapeutic managements.
Source: Neuro-Oncology
Authors: Lucie Auffret, Clémentine Barry, Yassine Ajlil, Arnault Tauziède-Espariat, Lisa Mayr, Marie Simbozel, Thomas Kergrohen, Chloé Puiseux, Laurent Riffaud, Pascale Blouin, Anne-Isabelle Bertozzi, Pierre Leblond, Klas Blomgren, Sébastien Froelich, Alberto Picca, Mehdi Touat, Marc Sanson, Kevin Beccaria, Thomas Blauwblomme, Volodia Dangouloff-Ros, Nathalie Boddaert, Johannes Gojo, Mariella Filbin, Pascale Varlet, Marie-Anne Debily, Jacques Grill, David Castel
Institutions: Institut Gustave Roussy, Fondation Gustave Roussy, GHU Paris psychiatrie & neurosciences, Dana-Farber Cancer Institute, Medical University of Vienna, Centre Hospitalier Universitaire de Rennes, Centre Hospitalier Universitaire de Tours, Hôpital des Enfants, Centre Léon Bérard, Karolinska University Hospital, Assistance Publique – Hôpitaux de Paris, Hôpital Lariboisière, Institut du Cerveau, Hôpital Necker-Enfants Malades
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4404230683