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^{1,2,3,4,5,6,7,8,9}, 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.

影响成纤维细胞生长因子受体 2（由FGFR2编码）的体细胞热点突变和结构扩增与融合发生在多种类型的癌症中¹。然而，对 FGFR 抑制剂的临床反应仍然存在^{差异 1,2,3,4,5,6,7,8,9}，强调需要更好地了解哪些FGFR2改变具有致癌性和治疗靶向性。在这里，我们在小鼠中应用基于转座子的筛选^10,11和肿瘤建模^12,13，并发现Fgfr2外显子 18 (E18) 的截短是一种有效的驱动突变。人类致癌基因组数据集揭示了一组不同的FGFR2改变，包括重排、E1-E17 部分扩增和 E18 无义突变和移码突变，每一种都会导致 E18 截短的FGFR2 ( FGFR2 ^ΔE18 ) 的转录。FGFR2 ^ΔE18和全长变体的概要的体外和体内功能检查将FGFR2 -E18 截短确定为癌症中的单一驱动改变。相比之下，FGFR2全长扩增的致癌能力取决于协同驱动基因的独特情况。这表明产生稳定FGFR2 ^{ΔE18的基因组改变}变体是可操作的治疗靶点，我们在临床前小鼠和人类肿瘤模型以及临床试验中证实了这一点。我们建议，对于包含任何具有截短 E18 的FGFR2变体的癌症，应考虑用于 FGFR 靶向治疗。