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

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 Leon, Karthikeyan Murugesan, Meagan Montesion, Lee A. Albacker, Shakti H. Ramkissoon, Cornelis M. 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 ()
Additional contact information
April A. Apfelbaum: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Eric Morin: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Dominik Sturm: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Georges Ayoub: Dana-Farber Cancer Institute
Jeromy DiGiacomo: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Sher Bahadur: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Bhavyaa Chandarana: Jewish General Hospital
Phoebe C. Power: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Margaret M. Cusick: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Dana Novikov: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Prem Prabhakar: Dana-Farber Cancer Institute
Robert E. Jones: Dana-Farber Cancer Institute
Jayne Vogelzang: Dana-Farber Cancer Institute
Connor C. Bossi: Dana-Farber Cancer Institute
Seth Malinowski: Dana-Farber Cancer Institute
Lewis M. Woodward: Queen Mary University of London
Tania A. Jones: Queen Mary University of London
John Jeang: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Sarah W. Lamson: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Jared Collins: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Kelly Y. Cai: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Jacquelyn S. Jones: Dana-Farber Cancer Institute
Sehee Oh: Dana-Farber Cancer Institute
Hyesung Jeon: Dana-Farber Cancer Institute
Jinhua Wang: Dana-Farber Cancer Institute
Amy Cameron: Dana-Farber Cancer Institute
Patrick Rechter: Dana-Farber Cancer Institute
Angela Leon: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Karthikeyan Murugesan: Foundation Medicine Inc
Meagan Montesion: Foundation Medicine Inc
Lee A. Albacker: Foundation Medicine Inc
Shakti H. Ramkissoon: Foundation Medicine Inc
Cornelis M. Tilburg: a partnership between DKFZ and Heidelberg University Hospital
Emily C. Hardin: a partnership between DKFZ and Heidelberg University Hospital
Philipp Sievers: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Felix Sahm: German Cancer Research Center (DKFZ)
Kee Kiat Yeo: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Tom Rosenberg: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Susan N. Chi: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Karen D. Wright: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Steven Hébert: Jewish General Hospital
Sydney Peck: Orlando Health- Arnold Palmer Hospital for Children
Alberto Picca: Pitié Salpêtrière University Hospital
Valérie Larouche: CHU de Québec-Université Laval
Samuele Renzi: Chul-Québec
Sara J. Buhrlage: Dana-Farber Cancer Institute
Tejus A. Bale: Memorial Sloan Kettering Cancer Center
Amy A. Smith: Orlando Health- Arnold Palmer Hospital for Children
Mehdi Touat: Pitié Salpêtrière University Hospital
Nada Jabado: McGill University
Eric S. Fischer: Dana-Farber Cancer Institute
Michael J. Eck: Dana-Farber Cancer Institute
Lissa Baird: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
Olaf Witt: a partnership between DKFZ and Heidelberg University Hospital
Claudia L. Kleinman: Jewish General Hospital
Quang- De Nguyen: Dana-Farber Cancer Institute
Denise Sheer: Queen Mary University of London
Sanda Alexandrescu: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center
David T. W. Jones: Hopp Children’s Cancer Center Heidelberg (KiTZ)
Keith L. Ligon: Broad Institute of MIT and Harvard
Pratiti Bandopadhayay: Dana-Farber Cancer/Boston Children’s Cancer and Blood Disorders Center

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61820-z

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