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

Yoshiyuki Suehara, Maria Arcila, Lu Wang, Adnan Hasanovic, Daphne Ang, Tatsuo Ito, Yuki Kimura, Alexander Drilon, Udayan Guha, Valerie Rusch, Mark G. Kris, Maureen F. Zakowski, Naiyer Rizvi, Raya Khanin, Marc Ladanyi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)6599-6608
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number24
DOIs
Publication statusPublished - Dec 15 2012
Externally publishedYes

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Oncogenes
Protein-Tyrosine Kinases
Lung Neoplasms
Phosphotransferases
Reverse Transcriptase Polymerase Chain Reaction
Messenger RNA
Exons
Complementary DNA
RNA
Glioma
Cell Line
Adenocarcinoma of lung
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. / Suehara, Yoshiyuki; Arcila, Maria; Wang, Lu; Hasanovic, Adnan; Ang, Daphne; Ito, Tatsuo; Kimura, Yuki; Drilon, Alexander; Guha, Udayan; Rusch, Valerie; Kris, Mark G.; Zakowski, Maureen F.; Rizvi, Naiyer; Khanin, Raya; Ladanyi, Marc.

In: Clinical Cancer Research, Vol. 18, No. 24, 15.12.2012, p. 6599-6608.

Research output: Contribution to journalArticle

Suehara, Y, Arcila, M, Wang, L, Hasanovic, A, Ang, D, Ito, T, Kimura, Y, Drilon, A, Guha, U, Rusch, V, Kris, MG, Zakowski, MF, Rizvi, N, Khanin, R & Ladanyi, M 2012, 'Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions', Clinical Cancer Research, vol. 18, no. 24, pp. 6599-6608. https://doi.org/10.1158/1078-0432.CCR-12-0838
Suehara, Yoshiyuki ; Arcila, Maria ; Wang, Lu ; Hasanovic, Adnan ; Ang, Daphne ; Ito, Tatsuo ; Kimura, Yuki ; Drilon, Alexander ; Guha, Udayan ; Rusch, Valerie ; Kris, Mark G. ; Zakowski, Maureen F. ; Rizvi, Naiyer ; Khanin, Raya ; Ladanyi, Marc. / Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 24. pp. 6599-6608.
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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.",
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T1 - Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions

AU - Suehara, Yoshiyuki

AU - Arcila, Maria

AU - Wang, Lu

AU - Hasanovic, Adnan

AU - Ang, Daphne

AU - Ito, Tatsuo

AU - Kimura, Yuki

AU - Drilon, Alexander

AU - Guha, Udayan

AU - Rusch, Valerie

AU - Kris, Mark G.

AU - Zakowski, Maureen F.

AU - Rizvi, Naiyer

AU - Khanin, Raya

AU - Ladanyi, Marc

PY - 2012/12/15

Y1 - 2012/12/15

N2 - 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.

AB - 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.

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