Zingg, DanielDanielZinggBhin, JinhyukJinhyukBhinYemelyanenko, JuliaJuliaYemelyanenkoKas, Sjors MSjors MKasRolfs, FrankFrankRolfsLutz, CatrinCatrinLutzLee, Jessica KJessica KLeeKlarenbeek, SjoerdSjoerdKlarenbeekSilverman, Ian MIan MSilvermanAnnunziato, StefanoStefanoAnnunziatoChan, Chang SChang SChanPiersma, Sander RSander RPiersmaEijkman, TimoTimoEijkmanBadoux, MadelonMadelonBadouxGogola, EwaEwaGogolaSiteur, BjørnBjørnSiteurSprengers, JustinJustinSprengersde Klein, BimBimde Kleinde Goeij-de Haas, Richard RRichard Rde Goeij-de HaasRiedlinger, Gregory MGregory MRiedlingerKe, HuaHuaKeMadison, RussellRussellMadisonDrenth, Anne PaulienAnne PaulienDrenthvan der Burg, ElineElinevan der BurgSchut, EvaEvaSchutHenneman, LindaLindaHennemanvan Miltenburg, Martine HMartine Hvan MiltenburgProost, NatalieNatalieProostZhen, HuilingHuilingZhenWientjens, EllenEllenWientjensde Bruijn, RoebiRoebide Bruijnde Ruiter, Julian RJulian Rde RuiterBoon, UteUteBoonde Korte-Grimmerink, RenskeRenskede Korte-Grimmerinkvan Gerwen, BastiaanBastiaanvan GerwenFéliz, LuisLuisFélizAbou-Alfa, Ghassan KGhassan KAbou-AlfaRoss, Jeffrey SJeffrey SRossvan de Ven, MariekeMariekevan de VenRottenberg, SvenSvenRottenberg0000-0003-2044-9844Cuppen, EdwinEdwinCuppenChessex, Anne VaslinAnne VaslinChessexAli, Siraj MSiraj MAliBurn, Timothy CTimothy CBurnJimenez, Connie RConnie RJimenezGanesan, ShridarShridarGanesanWessels, Lodewyk F ALodewyk F AWesselsJonkers, JosJosJonkers2024-10-112024-10-112022-08https://boris-portal.unibe.ch/handle/20.500.12422/86647Somatic 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.en600 - Technology::610 - Medicine & health600 - Technology::630 - Agriculturearticle10.48350/1719113594863310.1038/s41586-022-05066-5