Jang Jin Sung, Lee Adam, Li Jun, Liyanage Hema, Yang Yanan, Guo Lixia, Asmann Yan W, Li Peter W, Erickson-Johnson Michele, Sakai Yuta, Sun ZhiFu, Jeon Hyo-Sung, Hwang Hayoung, Bungum Aaron O, Edell Eric S, Simon Vernadette A, Kopp Karla J, Eckloff Bruce, Oliveira Andre M, Wieben Eric, Aubry Marie Christine, Yi Eunhee, Wigle Dennis, Diasio Robert B, Yang Ping, Jen Jin
Departments of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
Sci Rep. 2015 May 18;5:9755. doi: 10.1038/srep09755.
Lung adenocarcinomas from never smokers account for approximately 15 to 20% of all lung cancers and these tumors often carry genetic alterations that are responsive to targeted therapy. Here we examined mutation status in 10 oncogenes among 89 lung adenocarcinomas from never smokers. We also screened for oncogene fusion transcripts in 20 of the 89 tumors by RNA-Seq. In total, 62 tumors had mutations in at least one of the 10 oncogenes, including EGFR (49 cases, 55%), K-ras (5 cases, 6%), BRAF (4 cases, 5%), PIK3CA (3 cases, 3%), and ERBB2 (4 cases, 5%). In addition to ALK fusions identified by IHC/FISH in four cases, two previously known fusions involving EZR- ROS1 and KIF5B-RET were identified by RNA-Seq as well as a third novel fusion transcript that was formed between exons 1-9 of SND1 and exons 2 to 3' end of BRAF. This in-frame fusion was observed in 3/89 tested tumors and 2/64 additional never smoker lung adenocarcinoma samples. Ectopic expression of SND1-BRAF in H1299 cells increased phosphorylation levels of MEK/ERK, cell proliferation, and spheroid formation compared to parental mock-transfected control. Jointly, our results suggest a potential role of the novel BRAF fusion in lung cancer development and therapy.
从不吸烟的人患肺腺癌的病例约占所有肺癌病例的15%至20%，这些肿瘤往往携带对靶向治疗有反应的基因改变。在此，我们检测了89例从不吸烟的肺腺癌患者中10种致癌基因的突变状态。我们还通过RNA测序在89个肿瘤中的20个中筛查了致癌基因融合转录本。总共有62个肿瘤在10种致癌基因中的至少一种发生了突变，包括表皮生长因子受体（EGFR，49例，55%）、K-鼠肉瘤病毒癌基因同源物（K-ras，5例，6%）、B-Raf原癌基因（BRAF，4例，5%）、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA，3例，3%）和人表皮生长因子受体2（ERBB2，4例，5%）。除了通过免疫组化/荧光原位杂交在4例中鉴定出的间变性淋巴瘤激酶（ALK）融合外，通过RNA测序还鉴定出了两种先前已知的涉及Ezrin-ROS1和驱动蛋白家族成员5B-重排型转染期间重排（KIF5B-RET）的融合，以及第三种新的融合转录本，该转录本在含SND1结构域蛋白1（SND1）的第1至9外显子与BRAF的第2外显子至3'末端之间形成。在89个检测肿瘤中的3个以及另外64个从不吸烟的肺腺癌样本中的2个中观察到了这种读码框内融合。与亲本空载体转染对照相比，SND1-BRAF在人肺癌细胞系（H1299）细胞中的异位表达增加了丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK/ERK）的磷酸化水平、细胞增殖和球体形成。综合来看，我们的结果表明这种新的BRAF融合在肺癌发生发展和治疗中具有潜在作用。
