Whole-exome sequencing of familial non-small cell lung cancer patients with the EGFR gene mutations

• Project/Area Number: 17K16037
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Tode Naoki 東北大学, 東北メディカル・メガバンク機構, 非常勤講師 (00732223)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: EGFR遺伝子変異 / 肺癌 / エクソンシークエンス / 家族性肺癌 / EGFR / エクソームシークエンス

Outline of Final Research Achievements

Incidence of lung cancers with epidermal growth factor receptor (EGFR) gene mutations seems to depend on genetic background. To gain an insight into the genetic factors, we have performed whole exome sequencing of peripheral blood DNA from 8 patients with familial adenocarcinoma positive for EGFR gene mutations, 2 unaffected siblings and 2 unrelated healthy individuals.
In the present study, we identified a de novo MET mutation coding for N375K. We demonstrate that the mutated MET reduces the affinity for hepatocyte growth factor. The wild-type-transduced lung cancer H1299 cells increased the MET-mediated cellular activities including proliferation, migration and invasion, whereas the mutant-transduced cells did not. Consistently, MET-mediated activation of the HER2/PI3K/AKT signaling pathway was attenuated to some extent in H1299 cells expressing the mutated MET gene.

Academic Significance and Societal Importance of the Research Achievements

EGFR遺伝子変異陽性肺癌は，チロシンキナーゼ阻害薬(TKI)によって制御可能な癌と捉えられるようになった。一方で、肺腺癌の約25％がEGFR-TKIに自然耐性を示すとされ、かつ奏功症例においてもその大半が1年程度で耐性を獲得して再発することが知られており、実臨床の場において耐性化の克服が喫緊の課題となっている。
今回、EGFR遺伝子変異陽性肺癌の家族例に対してゲノム解析を行うことで、その責任遺伝子異常の同定を試みた。今後さらに研究をすすめることで責任遺伝子が明らかとなれば，①新しい治療標的を創出できるだけでなく、②採血するだけの非侵襲的な検査で③発症リスクの評価が可能となる。

Research Products

• [Journal Article] Inhaled GM-CSF for Pulmonary Alveolar Proteinosis (2019)
  • Author(s): Tazawa R、Ueda T、Abe M、Tatsumi K、Eda R、Kondoh S、Morimoto K、Tanaka T、Yamaguchi E、Takahashi A、Oda M、Ishii H、Izumi S、Sugiyama H、Nakagawa A、Tomii K、Suzuki M、Konno S、Ohkouchi S、Tode N、Handa T、Hirai T、Inoue Y、Arai T、Asakawa K、Sakagami T、Hashimoto A、Tanaka T、Takada T、Mikami A、Kitamura N、Nakata K
  • Journal Title: New England Journal of Medicine Volume: 381 Issue: 10 Pages: 923-932
  • DOI: 10.1056/nejmoa1816216
  • NAID: 120007087887
  • Peer Reviewed / Open Access
• [Journal Article] Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer. (2017)
  • Author(s): Tode N, Kikuchi T, Sakakibara T, Hirano T, Inoue A, Ohkouchi S, Tamada T, Okazaki T, Koarai A, Sugiura H, Niihori T, Aoki Y, Nakayama K, Matsumoto K, Matsubara Y, Yamamoto M, Watanabe A, Nukiwa T, Ichinose M.
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 6 Pages: 1263-1270
  • DOI: 10.1111/cas.13233
  • Peer Reviewed / Open Access / Acknowledgement Compliant