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RET, ROS1 and ALK fusions in lung cancer

Nature Medicine volume 18, pages 378–381 (2012)Cite this article

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Abstract

Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion–positive and 13 ROS1-fusion–positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion–positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥50 years, male sex, high pathological stage and negative kinase-fusion status.

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Figure 1: Identification of ROS1 fusions.
Figure 2: Discovery of RET fusions.

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Acknowledgements

We thank M. Iwakoshi, K. Shiozawa, T. Kakita, H. Nagano and K. Nomura for their technical assistance and S. Sengoku for providing administrative assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, as well as by grants from the Japan Society for the Promotion of Science; the Ministry of Health, Labor and Welfare of Japan; the Vehicle Racing Commemorative Foundation of Japan; the Princess Takamatsu Cancer Research Fund; and the Uehara Memorial Foundation.

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Author notes

  1. Yukitoshi Satoh

    Present address: Present address: Department of Thoracic Surgery, Kitasato University School of Medicine, Kanagawa, Japan.,

Authors and Affiliations

  1. Pathology Project for Molecular Targets, the Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    Kengo Takeuchi, Yuki Togashi, Seiji Sakata, Satoko Hatano & Reimi Asaka

  2. Division of Pathology, the Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    Kengo Takeuchi, Yuki Togashi, Reimi Asaka, Wakako Hamanaka, Hironori Ninomiya & Yuichi Ishikawa

  3. Division of Functional Genomics, Jichi Medical University, Tochigi, Japan

    Manabu Soda & Hiroyuki Mano

  4. Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Ritsuro Suzuki

  5. Department of Thoracic Surgical Oncology, Thoracic Center, the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Hirofumi Uehara, Yukitoshi Satoh, Sakae Okumura & Ken Nakagawa

  6. Department of Medical Genomics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Young Lim Choi & Hiroyuki Mano

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  1. Kengo Takeuchi
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Contributions

K.T. conceived of and led the entire project, designed the FISH probes, screened samples using FISH and immunohistochemistry, performed histopathological analyses, generated figures and tables and wrote the manuscript. M.S. performed functional analyses and generated the figures. Y.T. performed inverse RT-PCR and RACE experiments and their corresponding analyses. R.S. conducted statistical analyses. S.S. performed FISH and histopathological analyses. S.H. processed and analyzed the tissue microarrays and FISH screening and generated figures. R.A. processed the FISH probe library. W.H. made and analyzed the database and processed tissue microarrays. H.N., H.U., Y.S., S.O. and K.N. collected specimens and clinical information and were involved in planning the project. Y.L.C. conducted functional analyses. H.M. supervised the functional analyses and planned the project. Y.I. performed histopathological analyses and collected specimens. All authors participated in the discussion and interpretation of the data and the results.

Corresponding author

Correspondence to Kengo Takeuchi.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1–4, Supplementary Methods and Supplementary Appendix (PDF 4701 kb)

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Takeuchi, K., Soda, M., Togashi, Y. et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 18, 378–381 (2012). https://doi.org/10.1038/nm.2658

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