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A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterat...

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Main Authors: Apfelbaum, April (Author) , Morin, Eric (Author) , Sturm, Dominik (Author) , Ayoub, Georges (Author) , DiGiacomo, Jeromy (Author) , Bahadur, Sher (Author) , Chandarana, Bhavyaa (Author) , Power, Phoebe C. (Author) , Cusick, Margaret M. (Author) , Novikov, Dana (Author) , Prabhakar, Prem (Author) , Jones, Robert E. (Author) , Vogelzang, Jayne (Author) , Bossi, Connor C. (Author) , Malinowski, Seth (Author) , Woodward, Lewis M. (Author) , Jones, Tania A. (Author) , Jeang, John (Author) , Lamson, Sarah W. (Author) , Collins, Jared (Author) , Cai, Kelly Y. (Author) , Jones, Jacquelyn S. (Author) , Oh, Sehee (Author) , Jeon, Hyesung (Author) , Wang, Jinhua (Author) , Cameron, Amy (Author) , Rechter, Patrick (Author) , De Leon, Angela (Author) , Murugesan, Karthikeyan (Author) , Montesion, Meagan (Author) , Albacker, Lee A. (Author) , Ramkissoon, Shakti H. (Author) , Tilburg, Cornelis M. van (Author) , Hardin, Emily Cecilia (Author) , Sievers, Philipp (Author) , Sahm, Felix (Author) , Yeo, Kee Kiat (Author) , Rosenberg, Tom (Author) , Chi, Susan N. (Author) , Wright, Karen D. (Author) , Hébert, Steven (Author) , Peck, Sydney (Author) , Picca, Alberto (Author) , Larouche, Valérie (Author) , Renzi, Samuele (Author) , Buhrlage, Sara J. (Author) , Bale, Tejus A. (Author) , Smith, Amy A. (Author) , Touat, Mehdi (Author) , Jabado, Nada (Author) , Fischer, Eric S. (Author) , Eck, Michael J. (Author) , Baird, Lissa (Author) , Witt, Olaf (Author) , Kleinman, Claudia L. (Author) , Nguyen, Quang-De (Author) , Sheer, Denise (Author) , Alexandrescu, Sanda (Author) , Jones, David T. W. (Author) , Ligon, Keith L. (Author) , Bandopadhayay, Pratiti (Author)
Format: Article (Journal)
Language:English
Published: 31 July 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-23
ISSN:2041-1723
DOI:10.1038/s41467-025-61820-z
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-61820-z
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-61820-z
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Author Notes:April A. Apfelbaum, Eric Morin, Dominik Sturm, Georges Ayoub, Jeromy DiGiacomo, Sher Bahadur, Bhavyaa Chandarana, Phoebe C. Power, Margaret M. Cusick, Dana Novikov, Prem Prabhakar, Robert E. Jones, Jayne Vogelzang, Connor C. Bossi, Seth Malinowski, Lewis M. Woodward, Tania A. Jones, John Jeang, Sarah W. Lamson, Jared Collins, Kelly Y. Cai, Jacquelyn S. Jones, Sehee Oh, Hyesung Jeon, Jinhua Wang, Amy Cameron, Patrick Rechter, Angela De Leon, Karthikeyan Murugesan, Meagan Montesion, Lee A. Albacker, Shakti H. Ramkissoon, Cornelis M. van Tilburg, Emily C. Hardin, Philipp Sievers, Felix Sahm, Kee Kiat Yeo, Tom Rosenberg, Susan N. Chi, Karen D. Wright, Steven Hébert, Sydney Peck, Alberto Picca, Valérie Larouche, Samuele Renzi, Sara J. Buhrlage, Tejus A. Bale, Amy A. Smith, Mehdi Touat, Nada Jabado, Eric S. Fischer, Michael J. Eck, Lissa Baird, Olaf Witt, Claudia L. Kleinman, Quang-De Nguyen, Denise Sheer, Sanda Alexandrescu, David T.W. Jones, Keith L. Ligon and Pratiti Bandopadhayay

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520 |a Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. 
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