Abstract
The neuregulin 1 (NRG1) fusion is a recently identified novel driver oncogene in invasive mucinous adenocarcinoma of the lung (IMA). After identification of a case of SLC3A2-NRG1 in a patient with IMA, we verified this fusion gene in a cohort of 59 patients with IMA. Targeted cancer panel sequencing and RT-PCR identified the possible coexistence of other driver oncogenes. Among 59 IMAs, we found 16 NRG1 fusions (13 SLC3A2-NRG1 and 3 CD74-NRG1). Of 16 patients with NRG1 fusions, concurrent KRAS codon 12 mutations were found in 10 cases. We also found concurrent NRAS Q61L mutation and EML4-ALK fusion in additional two cases with NRG1 fusions. When comparing overall survival (OS) according to the presence of NRG1 fusions showed that patients harboring NRG1 fusions had significantly inferior OS than those without NRG1 fusions (hazard ratio = 0.286; 95% confidence interval, .094 to .865). Ectopic expression of the SLC3A2-NRG1 fusion in lung cancer cells increased cell migration, proliferation and tumor growth in vitro and in xenograft models, suggesting oncogenic function for the fusion protein. We found that the SLC3A2-NRG1 fusion promoted ERBB2-ERBB3 phosphorylation and heteroduplex formation and activated the downstream PI3K/AKT/mTOR pathway through paracrine signaling. These findings suggested that the SLC3A2-NRG1 fusion was a driver in IMA with an important prognostic impact. SLC3A2-NRG1 should be considered a therapeutic target for patients with IMA.
Highlights
Lung cancer is the leading cause of cancerrelated death worldwide and is highly heterogeneous at the molecular level [1]
No significant differences in clinicopathological features were observed between neuregulin 1 (NRG1) fusion-positive and fusion-negative invasive mucinous adenocarcinoma of the lung (IMA)
We discovered the SLC3A2-NRG1 fusion in a pan-negative lung adenocarcinoma detected by conventional Sanger sequencing, we performed targeted cancer panel deep sequencing to identify possible coexistence with known mutations
Summary
Lung cancer is the leading cause of cancerrelated death worldwide and is highly heterogeneous at the molecular level [1]. Adenocarcinoma is the most common histological subtype of lung cancer, and subclassification is clinically important for deciding the best course of treatment [2]. Tumor genotype analysis has identified driver alterations in 60-80% of lung adenocarcinoma patients according to ethnicity and smoking status [3]. Most mutations are mutually exclusive and associated with sensitivity or resistance to specific targeted therapies. EGFR, ALK and ROS1 mutations are treatable with kinase inhibitors and are more common in never-smokers with lung adenocarcinoma [5,6,7]. Genotype-based approaches have contributed to a paradigm shift in the treatment of lung cancer. Tumor genotyping at disease presentation is currently used to select among available targeted therapies for patients with lung adenocarcinoma. Novel driver oncogene research is an active area of investigation
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