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 variable^1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening^10,11 and tumour modelling in mice^12,13, 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 (FGFR2^ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2^ΔE18 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 FGFR2^ΔE18 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.