The roles of miRNAs in lung cancer have not yet been explored systematically at the genome scale despite their important regulatory functions. Here, we report an integrative analysis of miRNA and mRNA sequencing data for matched tumor–normal samples from 109 Korean female patients with non‐small‐cell lung adenocarcinoma (LUAD). We produced miRNA sequencing (miRNA‐Seq) and RNA‐Seq data for 48 patients and RNA‐Seq data for 61 additional patients. Subsequent differential expression analysis with stringent criteria yielded 44 miRNAs and 2322 genes. Integrative gene set analysis of the differentially expressed miRNAs and genes using miRNA–target information revealed several regulatory processes related to the cell cycle that were targeted by tumor suppressor miRNAs (TSmiR). We performed colony formation assays in A549 and NCI‐H460 cell lines to test the tumor‐suppressive activity of downregulated miRNAs in cancer and identified 7 novel TSmiRs (miR‐144‐5p, miR‐218‐1‐3p, miR‐223‐3p, miR‐27a‐5p, miR‐30a‐3p, miR‐30c‐2‐3p, miR‐338‐5p). Two miRNAs, miR‐30a‐3p and miR‐30c‐2‐3p, showed differential survival characteristics in the Tumor Cancer Genome Atlas (TCGA) LUAD patient cohort indicating their prognostic value. Finally, we identified a network cluster of miRNAs and target genes that could be responsible for cell cycle regulation. Our study not only provides a dataset of miRNA as well as mRNA sequencing from the matched tumor–normal samples, but also reports several novel TSmiRs that could potentially be developed into prognostic biomarkers or therapeutic RNA drugs.

VAMP2-NRG1 is a novel oncogenic fusion gene representing a new addition to the list of NRG1 fusion genes, which together may form an important diagnostic and clinical category of lung adenocarcinoma cases.

Neuregulin 1 (NRG1) has been discovered as the tail moiety of fusion genes with several distinct partner head genes in lung cancers. These fusion genes activate ERBB2/ERBB3 receptor-mediated cell signaling and thereby function as oncogenic drivers. We have carried out whole-transcriptome sequencing of 100 non-small cell lung carcinoma (NSCLC) tumors and isolated a novel fusion gene consisting of Vesicle-Associated Membrane Protein 2 (VAMP2) and NRG1. RT-PCR and genomic DNA analysis were used to demonstrate inter-chromosomal translocation. Immunoblotting and soft agar assays were used to examine stimulating activity of the fusion gene through ERBB2/ERBB3 signaling pathway. The most highly expressed splice variant of VAMP2-NRG1 fusion gene was shown to be membrane-bound and display EGF-like domain of NRG1 extracellularly. VAMP2-NRG1 promotes anchorage-independent colony formation of H1568 lung adenocarcinoma cells. Ectopic expression of the fusion gene stimulates phosphorylation of ERBB2 and ERBB3 as well as down-stream targets, AKT and ERK, confirming activation of the signaling pathway. VAMP2-NRG1 is a novel oncogenic fusion gene representing a new addition to the list of NRG1 fusion genes which together may form an important diagnostic and clinical category of lung adenocarcinoma cases. Citation Format: Yeonjoo Jung, Seunghui Yong, Pora Kim, Hee-Young Lee, Yeonhwa Jung, Juhee Keum, Suyeon Kim, Sanghyuk Lee, Jhingook Kim, Jaesang Kim. VAMP2-NRG1 fusion gene is a novel oncogenic driver of non-small cell lung adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-015. doi:10.1158/1538-7445.AM2015-LB-015