Investigation for tyrosine kinase mutations using novel methods

• Project/Area Number: 23659674
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Thoracic surgery
• Research Institution: Nagoya City University
• Principal Investigator: FUJII Yoshitaka 名古屋市立大学, 医学(系)研究科(研究院), 教授 (40156831)
• Co-Investigator(Kenkyū-buntansha): SASAKI Hidefumi 名古屋市立大学, 大学院医学研究科, 准教授 (00336695) ; YANO Motoki 名古屋市立大学, 大学院医学研究科, 准教授 (40315833) ; 矢野 智紀 名古屋市立大学, 医学(系)研究科(研究院), 准教授 (40315883)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2012: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2011: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: EGFR / RET / NTRK1 / BRAF / CAST-PCR / Immunohistochemistry / V600E / NTRK / NRF2 / KIF5B/RET / 肺癌 / FISH / CISH

Research Abstract

Molecular targeted therapies such as crizotinib that target ALK fusion and erlotinib or gefitinib that target EGFR mutations have demonstrated superior single agent activity in selected patients as compared to standard chemotherapy regimes in lung cancer treatment. Recently, a series of new gene fusions have been described in patients with lung cancer associated with the kinase domain of the RET and NTRK1 gene using next generation sequencing. We have developed FISH method to detect RET fusions. In our cohort three RET fusion mutants were found, all were female, non-smoker and adenocarcinomas. Point mutation of the BRAF gene is a genetic event in a subset of lung cancer. In addition, BRAF V600E is a driver mutation that can be effectively targeted with selective BRAF and/or MEK inhibitors. To determine the BRAF mutation status in Japanese lung carcinoma, we investigated BRAF V600E mutations by real time-PCR (CAST-PCR) and immunohistochemical methods using mutation specific antibody.

Research Products

• [Journal Article] Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. (2013)
  • Author(s): Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, Mahale S, Davies KD, Aisner DL, Pilling AB, Berge EM, Kim J, Sasaki H, Park S, Krykov G, Garraway LA, Hammerman PS, Haas J, Andrews SW, Lipson D, Stephens PJ, Miller VA, Varella-Garcia M, Janne P, Doebele RC.
  • Journal Title: Nature Medicine Volume: 19 Issue: 11 Pages: 1469-1472
  • DOI: 10.1038/nm.3352
  • Peer Reviewed
• [Journal Article] Usefulness of immunohistochemistry for the detection of the BRAF V600E mutation in Japanese lung adenocarcinoma (2013)
  • Author(s): Sasaki H, Shimizu S, Tani Y, Shitara M, Okuda K, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Lung Cancer Volume: 82(1) Issue: 1 Pages: 51-54
  • DOI: 10.1016/j.lungcan.2013.06.014
  • Peer Reviewed
• [Journal Article] Polymorphisms of NRF2 gene correlated with decreased FEV1 in lung cancers of smokers. (2013)
  • Author(s): Sasaki H, Suzuki A, Shitara M, Hikosaka Y, Okuda K, Moriyama S, Yano M, Fujii Y
  • Journal Title: Biomed Rep Volume: 1 Pages: 484-488
  • Peer Reviewed
• [Journal Article] RET expression and detection of KIF5B/RET gene rearrangements in Japanese lung cancer (2012)
  • Author(s): Sasaki H, Shimizu S, Tani Y, Maekawa M, Okuda K, Yokota K, Shitara M, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Cancer Med Volume: 1(1) Issue: 1 Pages: 68-75
  • DOI: 10.1002/cam4.13
  • Peer Reviewed
• [Journal Article] Braf and erbB2 mutations correlate with smoking status in lung cancer patients (2012)
  • Author(s): Sasaki H, Shitara M, Yokota K, Okuda K, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Exp Ther Med Volume: 3(5) Pages: 771-775
  • Peer Reviewed
• [Journal Article] KIF5B/RET fusion gene in surgically-treated adenocarcinoma of the lung (2012)
  • Author(s): Yokota K, Sasaki H, Okuda K, Shimizu S, Shitara M, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Oncol Rep Volume: 28(4) Issue: 4 Pages: 1187-1192
  • DOI: 10.3892/or.2012.1908
  • Peer Reviewed
• [Journal Article] Identification of new ALK and RET fusions from colorectal and lung cancer biopsies (2012)
  • Author(s): Lipson D, et al
  • Journal Title: Nat Med Volume: 18 Issue: 3 Pages: 382-384
  • DOI: 10.1038/nm.2673
  • Peer Reviewed
• [Journal Article] RagD gene expression and NRF2 mutations in lung squamous cell carcinomas (2012)
  • Author(s): Sasaki H, Shitara M, Yokota K, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Oncol Lett Volume: 4 Pages: 1167-1170
  • Peer Reviewed
• [Journal Article] DDR2 polymorphisms and mRNA expression in lung cancers of Japanese patients (2012)
  • Author(s): Sasaki H, Shitara M, Yokota K, Okuda K, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Oncol Lett Volume: 4 Pages: 33-37
  • Peer Reviewed
• [Journal Article] MRP3 gene expression correlates with NRF2 mutations in lung squamous cell carcinomas (2012)
  • Author(s): Sasaki H, Shitara M, Yokota K, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Journal Title: Mol Med Rep Volume: 6 Issue: 4 Pages: 705-708
  • DOI: 10.3892/mmr.2012.979
  • Peer Reviewed
• [Journal Article] Increased NRF2 gene (NFE2L2) copy number correlates with mutations in lung squamous cell carcinomas (2012)
  • Author(s): Sasaki H, Shitara M, Yokota K, Hikosaka Y, Moriyama S, Yano M, Fujii Y.
  • Journal Title: Mol Med Rep Volume: 6 Issue: 2 Pages: 391-394
  • DOI: 10.3892/mmr.2012.921
  • Peer Reviewed
• [Presentation] KIF5B/RET fusion gene in surgically-treated Japanese adenocarcinoma of the lung (2013)
  • Author(s): Sasaki H, Shimizu S, Tani Y, Okuda K, Hikosaka Y, Moriyama S, Yano M, Fujii Y
  • Organizer: 15thWorld Conference on Lung Cancer
  • Place of Presentation: Sydney,Australia
• [Presentation] 肺癌における新規599T挿入変異とダコエンビジョンフレックス系を用いたV600E 抗体による免疫組織学的検索 (2013)
  • Author(s): 佐々木秀文, 奥田勝裕, 森山 悟, 矢野智紀, 藤井義敬
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Dako Envision FLEX とBRAFV600E 特異的抗体を用いた肺癌におけるBRAF 遺伝子変異免疫組織学的検索 (2013)
  • Author(s): 佐々木秀文, 設楽将之, 奥田勝裕, 彦坂雄, 森山 悟, 矢野智紀, 藤井義敬
  • Organizer: 第66回日本胸部外科学会定期学術集会
  • Place of Presentation: 仙台
• [Presentation] 非小細胞肺癌におけるEGFRの遺伝子多型(SNP)に関する検討 (2012)
  • Author(s): 設楽将之、佐々木秀文、横田圭右、奥田勝裕、彦坂雄、森山悟、矢野智紀、藤井義敬
  • Organizer: 第５３回日本肺癌学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
• [Presentation] 肺癌患者におけるNRF2遺伝子コピー数の検討 (2012)
  • Author(s): 佐々木秀文、設楽将之、奥田勝裕、彦坂雄、森山悟、矢野智紀、藤井義敬
  • Organizer: 第５３回日本肺癌学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
• [Presentation] 肺癌の分子生物学における最近の進歩 日本人の肺腺癌におけるKIF5B/RET融合遺伝子 (2012)
  • Author(s): 横田圭右、佐々木秀文、奥田勝裕，設楽将之、彦坂雄、森山悟、矢野智紀、藤井義敬
  • Organizer: 第５３回日本肺癌学会総会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
• [Presentation] 日本人肺癌症例におけるRET発現とKIF5B/RET遺伝子転座の同定法 (2012)
  • Author(s): 奥田勝裕、佐々木秀文、矢野智紀、森山悟、彦坂雄、藤井義敬
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: ロイトン札幌ほか（札幌）
• [Presentation] 外科的切除を行った肺腺癌におけるLKB1遺伝子変異についての検討 (2012)
  • Author(s): 奥田勝裕、佐々木秀文、矢野智紀、森山悟、彦坂雄、横田圭右、設楽将之、藤井義敬
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張メッセほか（千葉）
• [Patent(Industrial Property Rights)] KIF5B 遺伝子とRET 遺伝子との間の転座を検出するFISH アッセイ (2012)
  • Inventor(s): 佐々木秀文
  • Industrial Property Rights Holder: 名古屋市立大学、ダコジャパン株式会社、株式会社GSP 研究所
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-01-27
• [Patent(Industrial Property Rights)] KIF5B遺伝子とRET遺伝子との間の転座を検出するFISHアッセイ (2012)
  • Inventor(s): 佐々木秀文
  • Industrial Property Rights Holder: 名古屋市立大学、ダコジャパン株式会社、株式会社GSP研究所
  • Filing Date: 2012