Clinical and molecular biological study of hereditary lung cancer caused by EGFR germline mutation

• Project/Area Number: 26462133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Kyorin University
• Principal Investigator: Ohtsuka Kouki 杏林大学, 医学部, 学内講師 (70439165)
• Co-Investigator(Kenkyū-buntansha): 渡邊 卓 杏林大学, 医学部, 教授 (00191768) ; 藤原 正親 杏林大学, 医学部, 准教授 (20407026) ; 横山 琢磨 杏林大学, 医学部, 学内講師 (50439197) ; 松島 早月 杏林大学, 医学部, 実験助手 (80231596) ; 大西 宏明 杏林大学, 医学部, 教授 (80291326)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: EGFR V843I germline変異 / 遺伝性肺癌症候群 / 次世代シーケンス / 全ゲノムシーケンス / 遺伝子改変マウス / 遺伝子変異導入細胞 / プロテオミクス / 分子シミュレーション

Outline of Final Research Achievements

We performed NGS in hereditary lung cancer syndrome caused by EGFR V843I germline mutaion, and revealed there is no carcinogenesis risk by cancer-related genes mutations other than EGFR and tumor of a proband with poor prognosis include TP53 R248W somatic mutation in addition to EGFR L858R, lung cancers of family members with good postoperative course have only EGFR V843I and L858R mutaions. We confirmed the proliferative capacity, tumorigenicity and activation of the EGFR signaling pathway of the cell line transfected with EGFR V843I and L858R mutations. Dynamic 3D docking simulation of EGFR V843I and L858R mutant protein and EGFR-TKIs was performed and it was predicted that existing EGFR-TKIs were ineffective. Similar results were obtained in the drug susceptibility test using the cultured lung cancer cell line established from the proband.

Research Products

• [Journal Article] V843I, a lung cancer predisposing EGFR mutation, is responsible for resistance to EGFR tyrosine kinase inhibitors (2014)
  • Author(s): S. Matsushima, K. Ohtsuka, H. Ohnishi, M. Fujiwara, H. Nakamura, T. Morii, H. Goto, T. Watanabe
  • Journal Title: J. Thor. Oncol. Volume: 9 Issue: 9 Pages: 1377-1384
  • DOI: 10.1097/jto.0000000000000241
  • Peer Reviewed
• [Presentation] EGFR V843I germline 変異をもつ遺伝性肺癌症例におけるWhole Genome Sequencing解析 (2016)
  • Author(s): 大塚弘毅
  • Organizer: 日本臨床検査医学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2016-09-01