Daniel Zingg # 1 2, Jinhyuk Bhin # 1 2 3, Julia Yemelyanenko # 1 2, Sjors M Kas # 1 2, Frank Rolfs 1 2 4, Catrin Lutz 1 2, Jessica K Lee 5, Sjoerd Klarenbeek 6, Ian M Silverman 7, Stefano Annunziato 1 2, Chang S Chan 8 9, Sander R Piersma 4, Timo Eijkman 1 2, Madelon Badoux 1 2, Ewa Gogola 1 2, Bjørn Siteur 10, Justin Sprengers 10, Bim de Klein 1 2, Richard R de Goeij-de Haas 4, Gregory M Riedlinger 9 11, Hua Ke 8 9, Russell Madison 5, Anne Paulien Drenth 1 2, Eline van der Burg 1 2, Eva Schut 1 2, Linda Henneman 1 2 10, Martine H van Miltenburg 1 2, Natalie Proost 10, Huiling Zhen 12, Ellen Wientjens 1 2, Roebi de Bruijn 1 2 3, Julian R de Ruiter 1 2 3, Ute Boon 1 2, Renske de Korte-Grimmerink 10, Bastiaan van Gerwen 10, Luis Féliz 13, Ghassan K Abou-Alfa 14 15, Jeffrey S Ross 5 16, Marieke van de Ven 10, Sven Rottenberg 1 17 18, Edwin Cuppen 2 19 20, Anne Vaslin Chessex 21, Siraj M Ali 5, Timothy C Burn 7, Connie R Jimenez 4, Shridar Ganesan 22 23, Lodewyk F A Wessels 24 25, Jos Jonkers 26 27
Affiliations
- 1Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- 2Oncode Institute, Utrecht, The Netherlands.
- 3Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- 4OncoProteomics Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- 5Foundation Medicine, Cambridge, MA, USA.
- 6Experimental Animal Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- 7Incyte Research Institute, Wilmington, DE, USA.
- 8Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
- 9Department of Medicine and Pharmacology, Rutgers University, Piscataway, NJ, USA.
- 10Mouse Clinic for Cancer and Aging, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- 11Department of Pathology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
- 12Incyte, Wilmington, DE, USA.
- 13Incyte Biosciences International, Morges, Switzerland.
- 14Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 15Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA.
- 16Upstate University Hospital, Upstate Medical University, Syracuse, NY, USA.
- 17Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
- 18Bern Center for Precision Medicine, University of Bern, Bern, Switzerland.
- 19Hartwig Medical Foundation, Amsterdam, The Netherlands.
- 20Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
- 21Debiopharm International, Lausanne, Switzerland.
- 22Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. ganesash@cinj.rutgers.edu.
- 23Department of Medicine and Pharmacology, Rutgers University, Piscataway, NJ, USA. ganesash@cinj.rutgers.edu.
- 24Oncode Institute, Utrecht, The Netherlands. l.wessels@nki.nl.
- 25Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, The Netherlands. l.wessels@nki.nl.
- 26Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands. j.jonkers@nki.nl.
- 27Oncode Institute, Utrecht, The Netherlands. j.jonkers@nki.nl.
- #Contributed equally.
PMID: 35948633 DOI: 10.1038/s41586-022-05066-5
Abstract
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.
