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Truncated FGFR2 is a clinically actionable oncogene in multiple cancers. 2022
Daniel Zingg, and
Jinhyuk Bhin, and
Julia Yemelyanenko, and
Sjors M Kas, and
Frank Rolfs, and
Catrin Lutz, and
Jessica K Lee, and
Sjoerd Klarenbeek, and
Ian M Silverman, and
Stefano Annunziato, and
Chang S Chan, and
Sander R Piersma, and
Timo Eijkman, and
Madelon Badoux, and
Ewa Gogola, and
Bjørn Siteur, and
Justin Sprengers, and
Bim de Klein, and
Richard R de Goeij-de Haas, and
Gregory M Riedlinger, and
Hua Ke, and
Russell Madison, and
Anne Paulien Drenth, and
Eline van der Burg, and
Eva Schut, and
Linda Henneman, and
Martine H van Miltenburg, and
Natalie Proost, and
Huiling Zhen, and
Ellen Wientjens, and
Roebi de Bruijn, and
Julian R de Ruiter, and
Ute Boon, and
Renske de Korte-Grimmerink, and
Bastiaan van Gerwen, and
Luis Féliz, and
Ghassan K Abou-Alfa, and
Jeffrey S Ross, and
Marieke van de Ven, and
Sven Rottenberg, and
Edwin Cuppen, and
Anne Vaslin Chessex, and
Siraj M Ali, and
Timothy C Burn, and
Connie R Jimenez, and
Shridar Ganesan, and
Lodewyk F A Wessels, and
Jos Jonkers
Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.
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Bjørn Siteur, and
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Richard R de Goeij-de Haas, and
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Hua Ke, and
Russell Madison, and
Anne Paulien Drenth, and
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Eva Schut, and
Linda Henneman, and
Martine H van Miltenburg, and
Natalie Proost, and
Huiling Zhen, and
Ellen Wientjens, and
Roebi de Bruijn, and
Julian R de Ruiter, and
Ute Boon, and
Renske de Korte-Grimmerink, and
Bastiaan van Gerwen, and
Luis Féliz, and
Ghassan K Abou-Alfa, and
Jeffrey S Ross, and
Marieke van de Ven, and
Sven Rottenberg, and
Edwin Cuppen, and
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Timothy C Burn, and
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Shridar Ganesan, and
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Jos Jonkers
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