Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions Journal Article


Authors: Suehara, Y.; Arcila, M.; Wang, L.; Hasanovic, A.; Ang, D.; Ito, T.; Kimura, Y.; Drilon, A.; Guha, U.; Rusch, V.; Kris, M. G.; Zakowski, M. F.; Rizvi, N.; Khanin, R.; Ladanyi, M.
Article Title: Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions
Abstract: Background: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist. We conducted a systematic search for tyrosine kinase fusions by screening all tyrosine kinases for aberrantly high RNA expression levels of the 3′ kinase domain (KD) exons relative to more 50 exons. Methods: We studied 69 patients (including five never smokers and 64 current or former smokers) with lung adenocarcinoma negative for allmajormutations in KRAS, EGFR, BRAF, MEK1, HER2, and for ALK fusions (termed "pan-negative"). A Nano String-based assaywas designed to query the transcripts of 9′ tyrosine kinases at two points: 5′ to the KD and within the KD or 3′ to it. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 30 to 50 expression ratios. Presumed novel fusion events were studied by rapid amplification of cDNA ends (RACE) and confirmatory reverse transcriptase PCR (RT-PCR) and FISH. Results: We identified one case each of aberrant 3′ to 5′ ratios in ROS1 and RET. RACE isolated a GOPC-ROS1 (FIG-ROS1) fusion in the former and a KIF5B-RET fusion in the latter, both confirmed by RT-PCR. The RET rearrangement was also confirmed by FISH. The KIF5B-RET patient was one of only five never smokers in this cohort. Conclusion: The KIF5B-RET fusion defines an additional subset of lung cancer with a potentially targetable driver oncogene enriched in never smokers with "pan-negative" lung adenocarcinomas. We also report in lung cancer the GOPC-ROS1 fusion originally discovered and characterized in a glioma cell line. ©2012 AACR.
Journal Title: Clinical Cancer Research
Volume: 18
Issue: 24
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2012-12-15
Start Page: 6599
End Page: 6608
Language: English
DOI: 10.1158/1078-0432.ccr-12-0838
PROVIDER: scopus
PUBMED: 23052255
PMCID: PMC4234119
DOI/URL:
Notes: --- - "Export Date: 2 January 2013" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Valerie W Rusch
    651 Rusch
  2. Naiyer A Rizvi
    156 Rizvi
  3. Marc Ladanyi
    862 Ladanyi
  4. Daphne Chua Ang
    14 Ang
  5. Maureen F Zakowski
    275 Zakowski
  6. Lu Wang
    139 Wang
  7. Raya Khanin
    38 Khanin
  8. Tatsuo Ito
    8 Ito
  9. Maria Eugenia Arcila
    336 Arcila
  10. Mark Kris
    597 Kris
  11. Alexander Edward Drilon
    136 Drilon
  12. Yuki Kimura
    1 Kimura