Apfelbaum April A, Morin Eric, Sturm Dominik, Ayoub Georges, DiGiacomo Jeromy, Bahadur Sher, Chandarana Bhavyaa, Power Phoebe C, Cusick Margaret M, Novikov Dana, Prabhakar Prem, Jones Robert E, Vogelzang Jayne, Bossi Connor C, Malinowski Seth, Woodward Lewis M, Jones Tania A, Jeang John, Lamson Sarah W, Collins Jared, Cai Kelly Y, Jones Jacquelyn S, Oh Sehee, Jeon Hyesung, Wang Jinhua, Cameron Amy, Rechter Patrick, De Leon Angela, Murugesan Karthikeyan, Montesion Meagan, Albacker Lee A, Ramkissoon Shakti H, van Tilburg Cornelis M, Hardin Emily C, Sievers Philipp, Sahm Felix, Yeo Kee Kiat, Rosenberg Tom, Chi Susan N, Wright Karen D, Hébert Steven, Peck Sydney, Picca Alberto, Larouche Valérie, Renzi Samuele, Buhrlage Sara J, Bale Tejus A, Smith Amy A, Touat Mehdi, Jabado Nada, Fischer Eric S, Eck Michael J, Baird Lissa, Witt Olaf, Kleinman Claudia L, Nguyen Quang-De, Sheer Denise, Alexandrescu Sanda, Jones David T W, Ligon Keith L, Bandopadhayay Pratiti
Department of Pediatric Oncology, Dana-Farber Cancer/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Commun. 2025 Jul 31;16(1):7018. doi: 10.1038/s41467-025-61820-z.
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.
成纤维细胞生长因子受体（FGFR）家族蛋白的致癌性改变在包括儿童胶质瘤在内的多种癌症中均有发生。我们对11635例不同年龄段胶质瘤进行的基因组分析发现，所有胶质瘤中有5.3%存在FGFR改变，在儿童胶质瘤中的发生率近9%。FGFR蛋白的改变在不同年龄、肿瘤分级和组织学类型中差异富集，其中FGFR1改变与神经胶质神经元组织学类型相关。利用同基因系统，我们证实FGFR1改变可诱导下游丝裂原活化蛋白激酶（MAPK）和mTOR信号通路，驱动胶质瘤发生，激活神经元转录程序，并对MAPK通路和泛FGFR抑制剂敏感。最后，我们对诊断为FGFR改变的胶质瘤儿童的临床反应进行了回顾性分析，发现使用现有抑制剂治疗主要与疾病稳定相关。本研究为FGFR1改变的胶质瘤生物学特性、针对它们的治疗策略以及仍需克服的相关挑战提供了关键见解。
