Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.
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.
Lung Cancer Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.|Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Dong Hoon
DH
Shin
Cancer Genomic Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Donghoon
D
Lee
Cancer Genomic Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Dong Wan
DW
Hong
Cancer Genomic Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Seung Hyun
SH
Hong
Cancer Genomic Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Jung-Ah
JA
Hwang
Biomolecular Function Research Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Byung Il
BI
Lee
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.
Hye Jin
HJ
You
Lung Cancer Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Geon Kook
GK
Lee
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
In-Hoo
IH
Kim
Cancer Genomic Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Yeon-Su
YS
Lee
Lung Cancer Branch, Graduate School of Cancer Science and Policy, National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
Ji-Youn
JY
Han
D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015331:Cohort Studies; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020890:Neuregulin-1 / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010766:Phosphorylation; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D027282:Fusion Regulatory Protein 1, Heavy Chain; C094131:NRG1 protein, human; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; C545989:SLC3A2 protein, human; D066246:ErbB Receptors
ERBB2; ERBB3; SLC3A2-NRG1; invasive mucinous adenocarcinoma (IMA)