ALK受体酪氨酸激酶(ALK)以外的多个癌基因融合,RET,ROS1融合已经在肺癌中被描述,特别是在没有常见致癌突变的肺腺癌中。分子抑制剂已经被开发出来,并被证明对肿瘤携带这些新变化的患者有效。
收集连续一系列手术切除的肺腺癌,并使用富集策略进行分析,以检测9种常见的致癌驱动突变和EGFR融合。KRAS,HER2BRAF,MET,ALK,RET,ROS1和FGFR。通过全面的基于RNA的下一代测序(NGS)融合分析进一步分析了驱动阴性病例的新型融合。
总共,我们分析了1681例肺腺癌,其中255例常见驱动阴性。77例病例有足够的组织进行NGS融合筛查,确定了八种小说融合。所有肺腺癌患者的NRG1融合发生率为0.36%(1681例中的6例),包括4例CD74-NRG1阳性病例,1例RBPMS-NRG1阳性病例,1例新的ITGB1-NRG1阳性病例。此外,还检测到另外两种新的融合,包括1个EGFR-SHC1融合和1个CD47-MET融合,两者都在框架内,并保留了相应激酶的功能域。未检测到NTRK的融合事件,KRAS,该队列中的BRAF或HER2基因。详细的临床病理数据显示,在新型融合中,浸润性黏液腺癌(八例中的三例)和腺泡占优势的腺癌(八例中的三例)是最常见的病理亚型。
影响NRG1、EGFR、在0.48%的未选择的肺腺癌中检测到MET,和NRG1融合在中国人群中常见的驾驶员阴性肺腺癌中排名最普遍的融合。基于RNA的NGS融合测定是用于在常见驱动阴性病例中筛选可操作融合的任选方法。
Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations.
A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based next-generation sequencing (NGS) fusion assay for novel fusions.
In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions.
Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.