Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung

Published on Sep 8, 2016in Oncotarget
· DOI :10.18632/ONCOTARGET.11913
Dong Hoon Shin1
Estimated H-index: 1
Dong Hoon Shin3
Estimated H-index: 3
+ 8 AuthorsJi-Youn Han32
Estimated H-index: 32
// Dong Hoon Shin 1,5 , Donghoon Lee 2 , Dong Wan Hong 2 , Seung Hyun Hong 2 , Jung-Ah Hwang 2 , Byung Il Lee 3 , Hye Jin You 4 , Geon Kook Lee 1 , In-Hoo Kim 5 , Yeon-Su Lee 2 and Ji-Youn Han 1 1 Lung Cancer Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea 2 Cancer Genomic Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea 3 Biomolecular Function Research Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea 4 Cancer Cell and Molecular Biology Branch, Research Institute and Hospital, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea 5 Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea Correspondence to: Ji-Youn Han, email: // Yeon-Su Lee, email: // Keywords : SLC3A2-NRG1, invasive mucinous adenocarcinoma (IMA), ERBB2, ERBB3 Received : March 15, 2016 Accepted : September 02, 2016 Published : September 08, 2016 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.
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