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Updated: May 1, 2026
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Druggable oncogene fusions in invasive mucinous lung adenocarcinoma
Takashi Nakaoku1, Koji Tsuta2, Hitoshi Ichikawa2
1Authors' Affiliations: Divisions of Genome Biology, Genetics, and Refractory Cancer Research, National Cancer Center Research Institute, Divisions of Pathology and Clinical Laboratories, Thoracic Surgery, and Thoracic Oncology, National Cancer Center Hospital, Chuo-ku; Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; and The Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, SpainAuthors' Affiliations: Divisions of Genome Biology, Genetics, and Refractory Cancer Research, National Cancer Center Research Institute, Divisions of Pathology and Clinical Laboratories, Thoracic Surgery, and Thoracic Oncology, National Cancer Center Hospital, Chuo-ku; Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan; Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; and The Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona, Spain.
Purpose:
To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur.
Experimental Design:
From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products.
Results:
We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use.
Conclusions:
Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs.
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