截断的FGFR2是多种癌症中临床上可作用的致癌基因

这表明产生稳定FGFR2ΔE18变体的基因组改变是可行的治疗目标，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，含有任何具有截断E18的FGFR2变体的癌症应考虑用于FGFR靶向治疗。Daniel Zingg, Jinhyuk Bhin, Julia Yemelyanenko, Sjors M. Kas, Frank Rolfs, Catrin Lutz, Jessica K. Lee, Sjoerd Klarenbeek, Ian M. Silverman, Stefano Annunziato, Chang S. Chan, Sander R. Piersma, Timo Eijkman, Madelon Badoux, Ewa Gogola, Bjørn Siteur, Justin Sprengers, Bim de Klein, Richard R. de Goeij-de Haas, Gregory M. Riedlinger, Hua Ke, Russell Madison, Anne Paulien Drenth, Eline van der Burg, Eva Schut, Linda Henneman, Martine H. van Miltenburg, Natalie Proost, Huiling Zhen, Ellen Wientjens, Roebi de Bruijn, Julian R. de Ruiter, Ute Boon, Renske de Korte-Grimmerink, Bastiaan van Gerwen, Luis Féliz, Ghassan K. Abou-Alfa, Jeffrey S. Ross, Marieke van de Ven, Sven Rottenberg, Edwin Cuppen, Anne Vaslin Chessex, Siraj M. Ali, Timothy C. Burn, Connie R. Jimenez, Shridar Ganesan, Lodewyk F. A. Wessels, Jos Jonkers CORRESPONDENCE TO; ganesash@cing.rutgers.edu, l.wessels@nki.nl, j.jonkers@nki.nlSomatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer. However, clinical responses to FGFR inhibitors have remained variable, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening and tumour modelling in mice and find that the truncation of exon 18 (E18) of Fg fr2 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.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、结构扩增和融合发生在多种类型的癌症中。然而，对FGFR抑制剂的临床反应仍然是多变的，强调需要更好地了解哪些FGFR2改变是致癌的和可用于治疗的。此处我们将基于转座子的筛选和肿瘤建模应用于小鼠，并发现Fgfr2的外显子18（E18）的截断是一种有效的驱动突变。人类癌基因组数据集显示了一组不同的FGFR2改变，包括重排、E1–E17部分扩增和E18无义和移码突变，每一种都导致E18截断FGFR2（FGFR2ΔE18）的转录。对FGFR2ΔE18和全长变体的功能性体外和体内检测表明，FGFR2-E18截断是癌症中的单一驱动因素改变。相反，FGFR2全长扩增的致癌能力取决于协同驱动基因的独特格局。这表明产生稳定FGFR2ΔE18变体的基因组改变是可行的治疗目标，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，含有任何具有截断E18的FGFR2变体的癌症应考虑用于FGFR靶向治疗。
（责任编辑：dawenwu）