小柯机器人

切换到桌面版
截断的FGFR2是多种癌症中一个临床可成药的癌基因
2022-08-14 22:43
来源：小柯机器人

荷兰癌症研究所Jos Jonkers等研究人员合作发现，截断的FGFR2是多种癌症中一个临床可成药的癌基因。该项研究成果于2022年8月10日在线发表在《自然》杂志上。

研究人员应用基于转座子的筛选和小鼠肿瘤模型，发现Fgfr2的第18外显子截断（E18）是一个强大的驱动突变。人类肿瘤基因组数据集显示了一系列不同的FGFR2改变，包括重排、E1-E17部分扩增、E18无义和框移突变，每一种都会导致E18截断的FGFR2（FGFR2ΔE18）的转录。对FGFR2ΔE18和全长变体的体外和体内功能筛查表明FGFR2-E18截断是癌症的单一驱动改变。相比之下，FGFR2全长扩增的致癌能力取决于合作驱动基因的独特状态。这表明，产生稳定的FGFR2ΔE18变体的基因组改变是可成药的治疗靶标，研究人员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。研究人员认为，含有任何截断E18的FGFR2变体的癌症都应考虑采用FGFR靶向治疗。
 
据悉，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及融合发生于多种类型的癌症。然而，对FGFR抑制剂的临床反应仍然是可变的，这强调需要更好地了解哪些FGFR2的改变是致癌的和可治疗的靶标。
 
附：英文原文
 
Title: Truncated FGFR2 is a clinically actionable oncogene in multiple cancers

Author: Zingg, Daniel, Bhin, Jinhyuk, Yemelyanenko, Julia, Kas, Sjors M., Rolfs, Frank, Lutz, Catrin, Lee, Jessica K., Klarenbeek, Sjoerd, Silverman, Ian M., Annunziato, Stefano, Chan, Chang S., Piersma, Sander R., Eijkman, Timo, Badoux, Madelon, Gogola, Ewa, Siteur, Bjrn, Sprengers, Justin, de Klein, Bim, de Goeij-de Haas, Richard R., Riedlinger, Gregory M., Ke, Hua, Madison, Russell, Drenth, Anne Paulien, van der Burg, Eline, Schut, Eva, Henneman, Linda, van Miltenburg, Martine H., Proost, Natalie, Zhen, Huiling, Wientjens, Ellen, de Bruijn, Roebi, de Ruiter, Julian R., Boon, Ute, de Korte-Grimmerink, Renske, van Gerwen, Bastiaan, Fliz, Luis, Abou-Alfa, Ghassan K., Ross, Jeffrey S., van de Ven, Marieke, Rottenberg, Sven, Cuppen, Edwin, Chessex, Anne Vaslin, Ali, Siraj M., Burn, Timothy C., Jimenez, Connie R., Ganesan, Shridar, Wessels, Lodewyk F. A., Jonkers, Jos

Issue&Volume: 2022-08-10

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 variable1,2,3,4,5,6,7,8,9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based 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.

DOI: 10.1038/s41586-022-05066-5

Source: https://www.nature.com/articles/s41586-022-05066-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

分享到:

0