Concurrence of FGFR1 mutations modulates oncogenesis in glioneuronal tumors
FGFR1 genetic alterations are associated with brain malignancies, including FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple concurrent FGFR1 mutations, we have mapped the proximal interactome of wild-type, single- and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveal novel oncogenic functionality for the two hotspot mutations N546K and K656E, linked to evasion of lysosomal degradation. Further, we identified a modulatory tumor-suppressive role for the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot N546K and K656E mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. Introducing the R661P missense variant was sufficient to abolish self-renewal capacity of oligodendroglioma cells and downregulate genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on contextual oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naive tumors.
Authors
- Cassandra J. Wong (ORCID: https://orcid.org/0009-0009-7292-3780)
- Jacopo Boni (ORCID: https://orcid.org/0000-0003-2626-9393)
- Cristina Rioja (ORCID: https://orcid.org/0000-0001-9713-1944)
- Martin Hasselblatt (ORCID: https://orcid.org/0000-0003-2707-8484)
- Jean‐François Côté (ORCID: https://orcid.org/0000-0001-7055-2642)
- Míriam Fernandez‐González (ORCID: https://orcid.org/0000-0003-4347-1761)
- Leticia Manen-Freixa (ORCID: https://orcid.org/0000-0001-7077-7657)
- Jonathan Boulais (ORCID: https://orcid.org/0000-0003-1848-0068)
- HyeRim Han (ORCID: https://orcid.org/0000-0003-2007-9222)
- Antonio Gómez
- Albert A. Antolín (ORCID: https://orcid.org/0000-0002-1634-9034)
- Clara Nogué (ORCID: https://orcid.org/0000-0002-5426-8809)
- Islam E. Elkholi (ORCID: https://orcid.org/0000-0002-8019-2481)
- Nada Jabado (ORCID: https://orcid.org/0000-0003-2485-3692)
- Endika Torres-Urtizberea (ORCID: https://orcid.org/0000-0001-8325-2032)
- Carla Roca (ORCID: https://orcid.org/0000-0003-1171-0588)
- Bárbara Rivera (ORCID: https://orcid.org/0000-0001-9434-6288)
- Anne‐Claude Gingras (ORCID: https://orcid.org/0000-0002-6090-4437)
- Roger Estrada‐Tejedor (ORCID: https://orcid.org/0000-0002-2983-0492)
Institutions
- Universitat de Vic - Universitat Central de Catalunya (ES)
- Mount Sinai Hospital (CA)
- Institute of Cancer Research (GB)
- University of Toronto (CA)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Cancer Research UK (GB)
- Jewish General Hospital (CA)
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- University Hospital Münster (DE)
- Institut Català d'Oncologia (ES)
- McGill Genome Centre (CA)
- Sinai Health System (CA)
- Institut Químic de Sarrià (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Montreal Clinical Research Institute (CA)
- McGill University (CA)
- Université de Montréal (CA)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1038/s44318-025-00600-3
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00