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Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Nakaoku, Takashi Tsuta, Koji Ichikawa, Hitoshi Shiraishi, Kouya Sakamoto, Hiromi Enari, Masato Furuta, Koh Shimada, Yoko Ogiwara, Hideaki Watanabe, Shun-ichi I. Nokihara, Hiroshi Yasuda, Kazuki Hiramoto, Masaki Nammo, Takao Ishigame, Teruhide Schetter, Aaron J. Okayama, Hirokazu Harris, Curtis C. Kim, Young Hak Mishima, Michiaki Yokota, Jun Yoshida, Teruhiko Kohno, Takashi |
| Copyright Year | 2014 |
| Abstract | 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. |
| Starting Page | 496 |
| Ending Page | 504 |
| Page Count | 9 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/20/12/3087.full.pdf |
| Alternate Webpage(s) | http://clincancerres.aacrjournals.org/content/clincanres/early/2014/04/11/1078-0432.CCR-14-0107.full.pdf |
| PubMed reference number | 24727320v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/1078-0432.CCR-14-0107 |
| DOI | 10.1158/1078-0432.ccr-14-0107 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Volume Number | 20 |
| Issue Number | 12 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Adenocarcinoma of lung (disorder) Anchorage Biopolymer Sequencing EZR gene Gene Fusion Mucinous Adenocarcinoma Mutation Non-Small Cell Lung Carcinoma Oncogene Fusion Oncogenes Protein Tyrosine Kinase Proto-Oncogene Proteins B-raf Receptor Tyrosine-Protein Kinase ErbB-4, human Structure of parenchyma of lung Tumorigenicity Whole Transcriptome Sequencing |
| Content Type | Text |
| Resource Type | Article |
