Abstract
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.
Highlights
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
In addition to ALK fusions identified by IHC/fluorescent in situ hybridization (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 39 end of BRAF
This study reports the high frequency of oncogene mutations and the identification of a novel SND1-BRAF fusion transcript in about 3% of lung adenocarcinoma from never smokers
Summary
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. 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 39 end of BRAF This in-frame fusion was observed in 3/89 tested tumors and 2/64 additional never smoker lung adenocarcinoma samples. NSCLC adenocarcinomas in female never smokers tend to have a much higher frequency of EGFR gene mutations and EML4-ALK transcript fusions[7] These patients benefit from targeted drugs such as gefinitib and crizotinib with significant tumor response and improved progression-free survival in advanced NSCLC over conventional therapy[7,8]. This study reports the high frequency of oncogene mutations and the identification of a novel SND1-BRAF fusion transcript in about 3% of lung adenocarcinoma from never smokers
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