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, Pratiti Bandopadhayay
{"title":"A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas","authors":"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, Pratiti Bandopadhayay","doi":"10.1038/s41467-025-61820-z","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"1 1","pages":""},"PeriodicalIF":15.7000,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-61820-z","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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