Study on molecular procedures developing oncogene fusion-positive lung cancer

• Project/Area Number: 26293200
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: National Cancer Center Japan
• Principal Investigator: Takashi Kohno 国立研究開発法人国立がん研究センター, その他部局等, その他 (80280783)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 遺伝子融合 / 肺がん / 非相同末端結合 / RET / 分子標的治療 / 遺伝子多型 / 癌 / 遺伝学 / ゲノム / 遺伝子変異 / ゲノム切断 / 染色体転座 / 染色体逆位 / ゲノム不安定性 / 発がん機構

Outline of Final Research Achievements

The purpose of this study was to elucidate molecular procedures for oncogene fusion and carcinogenic pathways developing oncogene fusion positive lung cancer. The driver fusion cases showed a distinct profile with smaller numbers of non-synonymous mutations in cancer-related genes, indicating that lung adenocarvinomas (LADCs) with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs. Structural analysis of breakpoint junctions of ALK, RET, and ROS1 fusions demonstrated that oncogene fusion is produced by illegitimate repair of DSBs at unspecified sites in genomic regions of a few kb through DNA synthesis-dependent or -independent end-joining pathways.

Research Products

• [Int'l Joint Research] University of Cologne(Germany)
• [Journal Article] Gene aberrations for precision medicine against lung adenocarcinoma. (2016)
  • Author(s): Saito M, Shiraishi K, Kunitoh H, Takenoshita S, Yokota J, Kohno T
  • Journal Title: Cancer Sci Volume: 107 Pages: 713-720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multiplex Diagnosis of Oncogenic Fusion and MET Exon Skipping by Molecular Counting Using Formalin-Fixed Paraffin Embedded Lung Adenocarcinoma Tissues. (2016)
  • Author(s): Sunami K, Furuta K, Tsuta K, Sasada S, Izumo T, Nakaoku T, Shimada Y, Saito M, Nokihara H, Watanabe S, Ohe Y, Kohno T
  • Journal Title: J Thorac Oncol Volume: 11 Pages: 203-12
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of Lung Adenocarcinomas with Exclusie Dependence on Oncogene Fusions. (2015)
  • Author(s): Motonobu Saito, Yoko Shimada, Kouya Shiraishi, Hiromi Sakamoto, Koji Tsuta, Hirohiko Totsuka, Suenori Chiku, Hitoshi Ichikawa, Mamoru Kato, Shun-ichi Watanabe, Teruhiko Yoshida, Jun Yokota, Takashi Kohno
  • Journal Title: Cancer Research Volume: - Issue: 11 Pages: 2264-2271
  • DOI: 10.1158/0008-5472.can-14-3282
  • Peer Reviewed
• [Journal Article] Molecular process producing oncogene fusion in lung cancer cells by illegitimate repair of DNA double-strand breaks. (2015)
  • Author(s): Seki Y, Mizukami T, Kohno T.
  • Journal Title: Biomolecules Volume: 5 Issue: 4 Pages: 2464-2476
  • DOI: 10.3390/biom5042464
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Development of Lung Adenocarcinomas with Exclusive Dependence on Oncogene Fusions. (2015)
  • Author(s): Saito M, Shimada Y, Shiraishi K, Sakamoto H, Tsuta K, Totsuka H, Chiku S, Ichikawa H, Kato M, Watanabe SI, Yoshida T, Yokota J, Kohno T.
  • Journal Title: Cancer Res Volume: 未確定
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis. (2014)
  • Author(s): Saito M, Ishigame T, Tsuta K, Kumamoto K, Imai T, Kohno T.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 11 Pages: 2452-2456
  • DOI: 10.1093/carcin/bgu158
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. (2014)
  • Author(s): Nakaoku T, Tsuta K, Ichikawa H, Shiraishi K, Sakamoto H, Enari M, Furuta K, Shimada Y, Ogiwara H, Watanabe S, Nokihara H, Yasuda K, Hiramoto M, Nammo T, Ishigame T, Schetter AJ, Okayama H, Harris CC, Kim YH, Mishima M, Yokota J, Yoshida T, Kohno T
  • Journal Title: Clin Cancer Res Volume: 20 Issue: 12 Pages: 3087-3093
  • DOI: 10.1158/1078-0432.ccr-14-0107
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 喫煙者、非喫煙者肺がんにおけるドライバー遺伝子異常の差異と発生機序 (2015)
  • Author(s): 河野隆志
  • Organizer: 第56回日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2015-11-26
  • Invited
• [Presentation] Personalized medicine of lung cancer using RET oncogene fusion and SWI/SNF chromatin remodeling deficiency (2014)
  • Author(s): Hideaki Ogiwara, Takashi Kohno
  • Organizer: 第５回日米修復会議
  • Place of Presentation: 徳島
  • Year and Date: 2014-10-28 – 2014-10-31
• [Presentation] Genetic aberration profile of lung adenocarcinoma with oncogenic ALK, RET, a nd ROS1 fusions (2014)
  • Author(s): Saito M, Kohno T
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Personalized medicine of lung cancer using RET oncogene fusion and SWI/SNF chromatin remodeling deficiency (2014)
  • Author(s): Kohno T
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Remarks] 融合遺伝子を標的としたがん治療法の開発（ゲノム生物学研究分野）
  • URL: http://www.nccri.ncc.go.jp/s010/010/010/20151209215834.html
• [Remarks] 分子診断・個別化医療開発グループ＿ゲノム生物学研究分野
  • URL: http://www.ncc.go.jp/jp/nccri/divisions/genome_biology/index.html