Yang Wenhui, Zhao Ximeng, Zheng Aiwen, Liu Zhengchuang, Ma Jie, Zhang Xiang, Li Wei, Wang Dan, Zhu Jianhua, Tao Houquan, Zhang Yanxiang, Ma Tonghui, Liu Qing
Department of Digestive Oncology, Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
Jichenjunchuang Clinical Laboratory, Hangzhou, China.
Int J Cancer. 2023 Mar 15;152(6):1259-1268. doi: 10.1002/ijc.34361. Epub 2022 Dec 8.
MET amplification and exon 14 skipping are well known as oncogenic drivers in multiple cancer types. However, MET fusions in most cancer types are poorly defined. To explore the profile and analyze the characteristics of MET fusions, a large-cohort study was conducted to screen MET fusions in clinical samples (n = 10 882) using DNA-based NGS. A total of 37 potentially functional MET fusions containing the intact tyrosine kinase domain (TKD) of MET were identified in 36 samples. Further, 15 novel MET fusions were identified in five cancer types, and the incidence of novel MET fusions accounted for 40.5% (15/37). Brain cancer had the highest incidence of MET fusion, with PTPRZ1-MET as the most common fusion (37.0%). All MET breakpoints in brain cancer (n = 27) were also located in intron 1, while those in lung cancer (n = 4) occurred in intron 1, intron 11, intron 14 and exon 14, respectively. The positive consistency of the common fusion group was 100% (11/11), while that of the rare fusion group was 53.8% (7/13). In conclusion, we provided a comprehensive genomic landscape of MET rearrangement and updated the MET fusions database for clinical test. In addition, we revealed that DNA-based NGS might serve as the clinical test for common MET fusions; however, rare MET fusions must be validated by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the treatment efficacy of MET inhibitors.
MET扩增和外显子14跳跃是多种癌症类型中众所周知的致癌驱动因素。然而，大多数癌症类型中的MET融合尚不清楚。为了探索MET融合的概况并分析其特征，我们进行了一项大型队列研究，使用基于DNA的二代测序（NGS）技术在临床样本（n = 10882）中筛选MET融合。在36个样本中总共鉴定出37种潜在功能性MET融合，其中包含MET完整的酪氨酸激酶结构域（TKD）。此外，在五种癌症类型中鉴定出15种新的MET融合，新MET融合的发生率占40.5%（15/37）。脑癌的MET融合发生率最高，其中PTPRZ1-MET是最常见的融合类型（37.0%）。脑癌中所有MET断点（n = 27）也都位于第1内含子，而肺癌中的MET断点（n = 4）分别发生在第1内含子、第11内含子、第14内含子和外显子14。常见融合组的阳性一致性为100%（11/11），而罕见融合组的阳性一致性为53.8%（7/13）。总之，我们提供了MET重排的全面基因组图谱，并更新了用于临床检测的MET融合数据库。此外，我们发现基于DNA的NGS可作为常见MET融合的临床检测方法；然而，罕见的MET融合必须通过基于DNA的NGS和基于RNA的NGS进行验证。需要进行前瞻性试验以确认MET抑制剂的治疗效果。
