Mutational analysis on carcinogenesis in multiple primary lung cancers

• Project/Area Number: 17K07176
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka City University
• Principal Investigator: Kawaguchi Tomoya 大阪市立大学, 大学院医学研究科, 教授 (70254422)
• Co-Investigator(Kenkyū-buntansha): 洪 泰浩 和歌山県立医科大学, 医学部, 准教授 (80426519)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肺癌 / 発がん / 環境因子 / ゲノム解析 / 非小細胞肺癌 / ゲノム異常 / 肺がん / 遺伝子変異 / 発癌

Outline of Final Research Achievements

We performed paired mutational analyses to clarify genetic mutations in multiple primary lung cancers (MPLC) and its relationship with environmental factors.
We obtained 38 surgical specimens from 17 patients who were pathologically diagnosed as MPLC and underwent surgery at Osaka City University Hospital. For genetic profiling of MPLC patients, the extracted DNAs were deep-sequenced for somatic mutations in 409 cancer-associated genes. The occurrence of concomitant EGFR or KRAS mutations in multiple tumors within the same individuals was significantly more frequent than expected by chance, suggesting environmental factors play more role in EGFR and KRAS mutations than the other mutations including TP53 which occurred more randomly in individual tumors. The development of EGFR or KRAS-mutated tumors were strongly related to environmental factors such as sex and smoking history, and suggested that the other mutations may occur randomly.

Academic Significance and Societal Importance of the Research Achievements

肺がん発癌に関与する環境因子としては喫煙がよく知られているが、喫煙によるゲノム異常から発癌へ至るメカニズムや、その他の環境因子の発癌における関与についての詳細は未だ明らかではない。本研究では肺がん発癌における環境因子の関与をさらに解明するために、同一症例における異所性、異時性同時性に発生した多発肺がん検体を用いてゲノム相同性の解析を行った。同じ環境因子下で発生した異なる肺がんの分子生物学的差異を明らかにし、発癌における環境因子の役割を解明する一助となった。

Research Products

• [Journal Article] Clinical Characteristics of Rapidly Progressive Fatal Hemorrhagic Pneumonia Caused by <i>Stenotrophomonas maltophilia</i> (2020)
  • Author(s): Imoto Waki、Yamada Koichi、Yamairi Kazushi、Shibata Wataru、Namikawa Hiroki、Yukawa Satomi、Yoshii Naoko、Nakaie Kiyotaka、Hirose Asao、Koh Hideo、Watanabe Tetsuya、Asai Kazuhisa、Nakamae Hirohisa、Kaneko Yukihiro、Kawaguchi Tomoya、Hino Masayuki、Kakeya Hiroshi
  • Journal Title: Internal Medicine Volume: 59 Issue: 2 Pages: 193-198
  • DOI: 10.2169/internalmedicine.3358-19
  • NAID: 130007785083
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-01-15
  • Peer Reviewed
• [Journal Article] Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors (2020)
  • Author(s): Matsumoto Yoshiya、Sawa Kenji、Fukui Mitsuru、Oyanagi Jun、Yoshimoto Naoki、Suzumura Tomohiro、Watanabe Tetsuya、Kaneda Hiroyasu、Mitsuoka Shigeki、Asai Kazuhisa、Kimura Tatsuo、Yamamoto Nobuyuki、Hirata Kazuto、Koh Yasuhiro、Kawaguchi Tomoya
  • Journal Title: Lung Cancer Volume: 139 Pages: 80-88
  • DOI: 10.1016/j.lungcan.2019.10.029
  • Peer Reviewed
• [Journal Article] Impact of somatic mutations on prognosis in resected non‐small‐cell lung cancer: The Japan Molecular Epidemiology for lung cancer study (2020)
  • Author(s): Tamiya Akihiro、Koh Yasuhiro、Isa Shun‐ichi、Kubo Akihito、Ando Masahiko、Saka Hideo、Yoshimoto Naoki、Takeo Sadanori、Adachi Hirofumi、Tagawa Tsutomu、Kawashima Osamu、Yamashita Motohiro、Kataoka Kazuhiko、Takenoyama Mitsuhiro、Takeuchi Yukiyasu、Watanabe Katsuya、Matsumura Akihide、Kawaguchi Tomoya
  • Journal Title: Cancer Medicine Volume: 9 Issue: 7 Pages: 2343-2351
  • DOI: 10.1002/cam4.2897
  • Peer Reviewed / Open Access
• [Journal Article] Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR ‐mutant non‐small cell lung cancer (2019)
  • Author(s): Matsumoto Yoshiya、Sawa Kenji、Fukui Mitsuru、Oyanagi Jun、Izumi Motohiro、Ogawa Koichi、Suzumura Tomohiro、Watanabe Tetsuya、Kaneda Hiroyasu、Mitsuoka Shigeki、Asai Kazuhisa、Kimura Tatsuo、Yamamoto Nobuyuki、Koh Yasuhiro、Kawaguchi Tomoya
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3244-3254
  • DOI: 10.1111/cas.14156
  • Peer Reviewed
• [Journal Article] Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L). (2019)
  • Author(s): Kimura T, Kawaguchi T, Chiba Y, Yoshioka H, Watanabe K, Kijima T, Kogure Y, Oguri T, Yoshimura N, Niwa T, Kasai T, Hayashi H, Ono A, Asai K, Tanaka H, Yano S, Yamamoto N, Nakanishi Y, Nakagawa K
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 49 Issue: 10 Pages: 947-955
  • DOI: 10.1093/jjco/hyz088
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficacy and safety of ultrasound (US) guided percutaneous needle biopsy for peripheral lung or pleural lesion: comparison with computed tomography (CT) guided needle biopsy (2019)
  • Author(s): Yamamoto Norio、Watanabe Tetsuya、Yamada Kazuhiro、Nakai Toshiyuki、Suzumura Tomohiro、Sakagami Kazuki、Yoshimoto Naoki、Sato Kanako、Tanaka Hidenori、Mitsuoka Shigeki、Asai Kazuhisa、Kimura Tatsuo、Kanazawa Hiroshi、Hirata Kazuto、Kawaguchi Tomoya
  • Journal Title: Journal of Thoracic Disease Volume: 11 Issue: 3 Pages: 936-943
  • DOI: 10.21037/jtd.2019.01.88
  • Peer Reviewed / Open Access
• [Journal Article] Exercise Ameliorates Emphysema Of Cigarette Smoke-Induced COPD In Mice Through The Exercise-Irisin-Nrf2 Axis. (2019)
  • Author(s): Kubo H, Asai K, Kojima K, Sugitani A, Kyomoto Y, Okamoto A, Yamada K, Ijiri N, Watanabe T, Hirata K, Kawaguchi T.
  • Journal Title: International Journal of COPD Volume: 14 Pages: 2507-2516
  • DOI: 10.2147/copd.s226623
  • Peer Reviewed / Open Access
• [Journal Article] Astaxanthin Suppresses Cigarette Smoke-Induced Emphysema through Nrf2 Activation in Mice. (2019)
  • Author(s): Kubo H, Asai K, Kojima K, Sugitani A, Kyomoto Y, Okamoto A, Yamada K, Ijiri N, Watanabe T, Hirata K, Kawaguchi T.
  • Journal Title: Marine Drugs Volume: 17 Issue: 12 Pages: 673-673
  • DOI: 10.3390/md17120673
  • Peer Reviewed / Open Access
• [Journal Article] Isoflavone Aglycones Attenuate Cigarette Smoke-Induced Emphysema via Suppression of Neutrophilic Inflammation in a COPD Murine Model. (2019)
  • Author(s): Kojima K, Asai K, Kubo H, Sugitani A, Kyomoto Y, Okamoto A, Yamada K, Ijiri N, Watanabe T, Hirata K, Kawaguchi T.
  • Journal Title: Nutrients Volume: 11 Issue: 9 Pages: 2023-2023
  • DOI: 10.3390/nu11092023
  • NAID: 120006716419
  • Peer Reviewed / Open Access
• [Journal Article] Handgrip strength measurement in patients with chronic obstructive pulmonary disease: Possible predictor of exercise capacity (2019)
  • Author(s): Kyomoto Yohkoh、Asai Kazuhisa、Yamada Kazuhiro、Okamoto Atsuko、Watanabe Tetsuya、Hirata Kazuto、Kawaguchi Tomoya
  • Journal Title: Respiratory Investigation Volume: 57 Issue: 5 Pages: 499-505
  • DOI: 10.1016/j.resinv.2019.03.014
  • NAID: 120006890446
  • Peer Reviewed
• [Journal Article] Chemotherapy versus erlotinib as second-line treatment in patients with advanced non-small cell lung cancer and wild-type epidermal growth factor receptor: an individual patient data (IPD) analysis (2018)
  • Author(s): Garassino Marina Chiara、Kawaguchi Tomoya、Gregorc Vanesa、Rulli Eliana、Ando Masahiko、Marsoni Silvia、Isa Shun-ichi、Novello Silvia、Farina Gabriella、Barni Sandro、Torri Valter、Cinquini Michela
  • Journal Title: ESMO Open Volume: 3 Issue: 6 Pages: e000327-e000327
  • DOI: 10.1136/esmoopen-2018-000327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dose Escalation Study of Concurrent Chemoradiotherapy With the Use of Involved-field Conformal Radiotherapy and Accelerated Hyperfractionation in Combination With Cisplatin and Vinorelbine Chemotherapy for Stage III Non?small Cell Lung Cancer (2018)
  • Author(s): Yoshimura Naruo、Tada Takuhito、Matsumoto Yoshiya、Sawa Kenji、Yoshimoto Naoki、Suzumura Tomohiro、Tanaka Hidenori、Mitsuoka Shigeki、Kimura Tatsuo、Tamiya Tomohiro、Hirashima Tomonori、Kawaguchi Tomoya、Kudoh Shinzoh、Hosono Masako、Hirata Kazuto
  • Journal Title: American Journal of Clinical Oncology Volume: 41 Issue: 10 Pages: 967-971
  • DOI: 10.1097/coc.0000000000000412
  • Peer Reviewed
• [Journal Article] Phase1 study of cisplatin plus pemetrexed with erlotinib and bevacizumab for chemotherapy-na?ve advanced non-squamous non-small cell lung cancer with EGFR mutations (2018)
  • Author(s): Tamiya Motohiro、Tamiya Akihiro、Shiroyama Takayuki、Takeoka Sawa、Naito Yujiro、Omachi Naoki、Kimura Yohei、Morishita Naoko、Suzuki Hidekazu、Okamoto Norio、Okishio Kyoichi、Kawaguchi Tomoya、Atagi Shinji、Hirashima Tomonori
  • Journal Title: Investigational New Drugs Volume: 36 Issue: 4 Pages: 608-614
  • DOI: 10.1007/s10637-017-0527-z
  • Peer Reviewed
• [Journal Article] 肺がん薬物療法の歴史とがん免疫療法の発展 (2018)
  • Author(s): 川口知哉、光岡茂樹、金田裕靖、鈴村倫弘、澤兼士、渡辺徹也、浅井一久
  • Journal Title: 大阪市医学会雑誌 Volume: 67 Pages: 7-14
  • NAID: 120006549652
• [Journal Article] PIK3CA mutation as a distinctive genetic feature of non-small cell lung cancer with chronic obstructive pulmonary disease: A comprehensive mutational analysis from a multi-institutional cohort (2017)
  • Author(s): Sawa Kenji、Koh Yasuhiro、Kawaguchi Tomoya、Kambayashi Satoshi、Asai Kazuhisa、Mitsuoka Shigeki、Kimura Tatsuo、Yoshimura Naruo、Yoshimoto Naoki、Kubo Akihito、Saka Hideo、Matsumura Akihide、Wanibuchi Hideki、Yamamoto Nobuyuki、Nishiyama Noritoshi、Hirata Kazuto
  • Journal Title: Lung Cancer Volume: 112 Pages: 96-101
  • DOI: 10.1016/j.lungcan.2017.07.039
  • Peer Reviewed / Open Access
• [Journal Article] Multiplex Ultrasensitive Genotyping of Patients with Non-Small Cell Lung Cancer for Epidermal Growth Factor Receptor (EGFR) Mutations by Means of Picodroplet Digital PCR (2017)
  • Author(s): Watanabe Masaru、Kawaguchi Tomoya、Isa Shun-ichi、Ando Masahiko、Tamiya Akihiro、Kubo Akihito、Saka Hideo、Takeo Sadanori、Adachi Hirofumi、Tagawa Tsutomu、Kawashima Osamu、Yamashita Motohiro、Kataoka Kazuhiko、Ichinose Yukito、Takeuchi Yukiyasu、Watanabe Katsuya、Matsumura Akihide、Koh Yasuhiro
  • Journal Title: EBioMedicine Volume: 21 Pages: 86-93
  • DOI: 10.1016/j.ebiom.2017.06.003
  • Peer Reviewed / Open Access
• [Journal Article] Association between environmental tobacco smoke exposure and the occurrence of EGFR mutations and ALK-rearrangements in never-smokers with non-small cell lung cancer: analyses from a prospective multinational ETS registry. (2017)
  • Author(s): Kubo A, Soo RA, Ando M, Kawaguchi T, Ahn MJ, Ou S-HI
  • Journal Title: Clin Lung Cancer Volume: 18 Issue: 5 Pages: 535-42
  • DOI: 10.1016/j.cllc.2017.01.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phase I/II study of docetaxel combined with resminostat, an oral hydroxamic acid HDAC inhibitor, for advanced non-small cell lung cancer in patients previously treated with platinum-based chemotherapy (2017)
  • Author(s): Tambo Yuichi、Hosomi Yukio、Sakai Hiroshi、Nogami Naoyuki、Atagi Shinji、Sasaki Yasutsuna、Kato Terufumi、Takahashi Toshiaki、Seto Takashi、Maemondo Makoto、Nokihara Hiroshi、Koyama Ryo、Nakagawa Kazuhiko、Kawaguchi Tomoya、Okamura Yuta、Nakamura Osamu、Nishio Makoto、Tamura Tomohide
  • Journal Title: Invest New Drugs Volume: 35 Issue: 2 Pages: 217-226
  • DOI: 10.1007/s10637-017-0435-2
  • Peer Reviewed
• [Presentation] Association between low-frequency pretreatment EGFR T790M mutation and tumor immune microenvironment in patients with EGFR-mutated non-small cell lung cancer. (2019)
  • Author(s): Yoshiya Matsumoto, Tomoya Kawaguchi, Yasuhiro Koh, Motohiro Izumi
  • Organizer: American Association for Cancer Research Annual Meeting
  • Int'l Joint Research
• [Presentation] Japan Molecular Epidemiology for lung cancer (JME) study and beyond (2018)
  • Author(s): Tomoya Kawaguchi
  • Organizer: The 1st Guangdong Association of Thoracic Disease Symposium for Multidisciplinary Therapy of Lung Cancer
  • Int'l Joint Research / Invited
• [Presentation] Impact of somatic mutations on recurrence free survival (RFS) and overall survival (OS) for resected non-small cell lung cancer (NSCLC): results from the Japan Molecular Epidemiology for lung cancer study (JME) (2018)
  • Author(s): Akihiro Tamiya, Yasuhiro Koh, Akihito Kubo, Masahiko Ando, Shun-ichi Isa, Hideo Saka, Naoki Yoshimoto, Masakuni Serizawa, Sadanori Takeo, Hirofumi Adachi, Tsutomu Tagawa,
  • Organizer: American Societry of Clinical Oncology
  • Int'l Joint Research
• [Presentation] Predictive impact of low-frequency pretreatment T790M mutation in patients with EGFR-mutated non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors (2018)
  • Author(s): Yoshiya Matsumoto, Kenji Sawa, Jun Oyanagi, Mitsuru Fukui, Naoki Yoshimoto, Tomohiro Suzumura, Shigeki Mitsuoka, Kazuhisa Asai, Tatsuo Kimura, Nobuyuki Yamamoto, Tomoya Kawaguchi, Kazuto Hirata, and Yasuhiro Koh
  • Organizer: American Association of Cancer Research
  • Int'l Joint Research
• [Presentation] Impact of de Novo T790M on Outcome for Resected NSCLC from EGFR Mutant Cohort of Japan Molecular Epidemiology (JME) Study (2018)
  • Author(s): Y. Matsumoto, T. Kawaguchi, K. Sawa, S. Isa, M. Ando, A. Tamiya, A. Kubo, H. Saka, A. Matsumura, Y. Koh
  • Organizer: World Congress of Lung Cancer
  • Int'l Joint Research
• [Presentation] molecular epidemiology (2017)
  • Author(s): Kawaguchi t
  • Organizer: 世界肺癌学会総会
  • Int'l Joint Research / Invited