Genome analysis of lung adenocarcinoma with particular reference to early lesions, etiology and driver mutations

• Project/Area Number: 19H03446
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: International University of Health and Welfare
• Principal Investigator: ISHIKAWA Yuichi 国際医療福祉大学, 医学部, 教授 (80222975)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 肺がん / 腺がん / 早期がん / がん関連遺伝子 / 変異シグナチャー / 喫煙 / 環境因子 / 全エクソンシークエンス / 変異シグネチャー / ホルマリン固定材料 / ゲノムシークエンス / 腺癌 / 早期病変 / ゲノム解析 / 肺癌 / 早期癌 / ドライバー変異 / 発癌因子 / 上皮内癌 / ドライバー遺伝子変異 / アスベスト / 石綿

Outline of Research at the Start

次世代シークエンスの発達により、癌の全エクソン解析が可能となった。ホルマリン固定パラフィン包埋材料（FFPE）での解析結果も安定してきた。本研究では、FFPEを使っての肺腺癌の早期病変、原因およびドライバー変異に焦点をあてた全エクソーム解析を行う。具体的には、(1) 喫煙者、非喫煙者、非喫煙アスベスト曝露者に発生した早期腺癌、(2)ALK肺癌を含む2重癌、ALK肺癌の進展に伴うゲノム変化を解析する。これにより、種々の原因による早期腺癌のゲノム変化、および同一患者にALK肺癌と別の肺癌が発生する機序、さらにALK肺癌のプログレッションに関連したゲノム変化が明らかになる。

Outline of Final Research Achievements

To investigate characteristic genetic changes of early lung adenocarcinoma, we examined cancer related genes and mutation signatures by whole exome sequence. Regarding cancer related genes, mutations of KRAS, BRAF and ERBB2 were detected in EGFR-wild tumors. Regarding mutation signatures, there were no significant increase of C/A substitutions in smokers’ EGFR-mutated tumors, and the SBS2/13 signature was noted. These may be novel characters of genetic signatures for smoking-unrelated tumors arising in smokers.

Academic Significance and Societal Importance of the Research Achievements

これまで解明されていなかった早期肺腺癌の遺伝子変化を解明することで、肺癌の原因に迫ることができる。本研究では、EGFR変異肺癌のなかで喫煙者と非喫煙者の癌を比べることで、喫煙者に発生したEGFR変異肺癌は、非喫煙者のEGFR変異肺癌とは異なる癌である可能性が示され、またEGFR陰性肺癌を特徴付ける新たなシグナチャーが抽出された可能性が浮上した。

Research Products

• [Journal Article] Estrogen Receptor-β Gene Cytosine-Adenine (ESR2-CA) Repeat Polymorphism in Postmenopausal Colon Cancer (2023)
  • Author(s): Honma Naoko、Arai Tomio、Matsuda Yoko、Fukunaga Yosuke、Muramatsu Masaaki、Ikeda Shinobu、Akishima-Fukasawa Yuri、Yamamoto Noriko、Kawachi Hiroshi、Ishikawa Yuichi、Takeuchi Kengo、Mikami Tetuo
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 5 Pages: 4502-4502
  • DOI: 10.3390/ijms24054502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The combined use of long non-coding RNA HOTAIR and polycomb group protein EZH2 as a prognostic marker of lung adenocarcinoma. (2022)
  • Author(s): Iizuka T, Nagano H, Nomura K, Hiramatsu M, Motoi N, Mun M, Ishikawa Y
  • Journal Title: Cancer Treat Res Commun Volume: 31 Pages: 100541-100541
  • DOI: 10.1016/j.ctarc.2022.100541
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Relationship Between Pathologic T1 Categories and Pathologic Factors Affecting Prognosis in Pulmonary Adenocarcinoma. (2022)
  • Author(s): Ninomiya H, Inamura K, Mun M, Nishio M, Ishikawa Y.
  • Journal Title: JTO Clin Res Rep. Volume: 10 Issue: 4 Pages: 100293-100293
  • DOI: 10.1016/j.jtocrr.2022.100293
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of epidermal growth factor receptor mutation and the presence of high-grade patterns is associated with recurrence in resected stage I lung adenocarcinoma (2022)
  • Author(s): Kondo Y, Ichinose J, Ninomiya H, Hashimoto K, Matsuura Y, Nakao M, Ishikawa Y, Okumura S, Satoh Y, Mun M
  • Journal Title: Interact Cardiovasc Thorac Surg Volume: 35 Issue: 2
  • DOI: 10.1093/icvts/ivac062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Estrogen concentration and estrogen receptor-β expression in postmenopausal colon cancer considering patient/tumor background (2022)
  • Author(s): Naoko Honma, Tomio Arai, Yoko Matsuda, Yosuke Fukunaga, Yuri Akishima-Fukasawa, Noriko Yamamoto, Hiroshi Kawachi, Yuichi Ishikawa, Kengo Takeuchi, Tetuo Mikami
  • Journal Title: J Cancer Res Clin Oncol Volume: 148 Issue: 5 Pages: 1063-1071
  • DOI: 10.1007/s00432-021-03889-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Elastin in pulmonary pathology: relevance in tumours with a lepidic or papillary appearance. A comprehensive understanding from a morphological viewpoint (2021)
  • Author(s): Thunnissen Erik、Motoi Noriko、Minami Yuko、Matsubara Daisuke、Timens Wim、Nakatani Yukio、Ishikawa Yuichi、Baez‐Navarro Ximena、Radonic Teodora、Blaauwgeers Hans、Borczuk Alain C、Noguchi Masayuki
  • Journal Title: Histopathology Volume: 80 Issue: 3 Pages: 457-467
  • DOI: 10.1111/his.14537
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monitoring epidermal growth factor receptor C797S mutation in Japanese non?small cell lung cancer patients with serial cell‐free DNA evaluation using digital droplet PCR (2021)
  • Author(s): Ariyasu Ryo、Uchibori Ken、Sasaki Takaaki、Tsukahara Mika、Kiyotani Kazuma、Yoshida Ryohei、Ono Yusuke、Kitazono Satoru、Ninomiya Hironori、Ishikawa Yuichi、Mizukami Yusuke、Yanagitani Noriko、Fujita Naoya、Nishio Makoto、Katayama Ryohei
  • Journal Title: Cancer Science Volume: - Issue: 6 Pages: 2371-2380
  • DOI: 10.1111/cas.14879
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel Histologic Classification of Small Tumor Cell Nests for Lung Adenocarcinoma With Prognostic and Etiological Significance (2021)
  • Author(s): Saito Ryoko、Ninomiya Hironori、Okumura Sakae、Mun Mingyon、Sasano Hironobu、Ishikawa Yuichi
  • Journal Title: American Journal of Surgical Pathology Volume: 45 Issue: 5 Pages: 604-615
  • DOI: 10.1097/pas.0000000000001696
  • Peer Reviewed
• [Journal Article] Histologic Classification of Tumors of the Pleura: How Has the WHO Classification Progressed After 2015? (2021)
  • Author(s): Ishikawa Yuichi
  • Journal Title: "Malignant pleural mesothelioma" ed. by Nakano T, Kijima T. Volume: - Pages: 89-99
  • DOI: 10.1007/978-981-15-9158-7_8
  • ISBN: 9789811591570, 9789811591587
  • Peer Reviewed
• [Journal Article] Frequent expression of conventional endothelial markers in pleural mesothelioma: usefulness of claudin-5 as well as combined traditional markers to distinguish mesothelioma from angiosarcoma (2020)
  • Author(s): Nakashima Yasuhiro、Inamura Kentaro、Ninomiya Hironori、Okumura Sakae、Mun Mingyon、Kirimura Susumu、Kobayashi Masashi、Okubo Kenichi、Ishikawa Yuichi
  • Journal Title: Lung Cancer Volume: 148 Pages: 20-27
  • DOI: 10.1016/j.lungcan.2020.07.029
  • Peer Reviewed
• [Journal Article] Calretinin-expressing lung adenocarcinoma: distinct characteristics of advanced stages, smoker-type features, and rare expression of other mesothelial markers are useful to differentiate epithelioid mesothelioma (2020)
  • Author(s): Matsuda M, Ninomiya H, Wakejima R, Inamura K, Okumura S, Mun M, Kitagawa M, Ishikawa Y
  • Journal Title: Pathol Res Pract Volume: 216 Issue: 3 Pages: 152817-152817
  • DOI: 10.1016/j.prp.2020.152817
  • Peer Reviewed
• [Journal Article] Insulinoma-associated protein 1 (INSM1) is a better marker for the diagnosis and prognosis estimation of small cell lung carcinoma than neuroendocrine phenotype markers such as chromogranin A, synaptophysin and CD56. (2020)
  • Author(s): Sakakibara R, Kobayashi M, Takahashi N, Inamura K, Ninomiya H, Wakejima R, Kitazono S, Yanagitani N, Horiike A, Ichinose J, Matsuura Y, Nakao M, Mun M, Nishio M, Okumura S, Motoi N, Ito T, Miyazaki Y, Inase N and Ishikawa Y.
  • Journal Title: Am J Surg Pathol Volume: - Issue: 6 Pages: 757-764
  • DOI: 10.1097/pas.0000000000001444
  • Peer Reviewed
• [Journal Article] Pathogenesis of Secondary Spontaneous Pneumothorax Complicating Osteosarcoma (2020)
  • Author(s): Matsuura Yosuke、Ninomiya Hironori、Ichinose Junji、Nakao Masayuki、Ishikawa Yuichi、Okumura Sakae、Mun Mingyon
  • Journal Title: The Annals of Thoracic Surgery Volume: 110 Issue: 2 Pages: e81-e83
  • DOI: 10.1016/j.athoracsur.2019.12.050
  • Peer Reviewed
• [Journal Article] Pulmonary mucoepidermoid carcinoma arising in a patient with Kartagener syndrome. (2020)
  • Author(s): Nagai Y, Koyama N, Iwai Y, Tsubochi H, Hiruta M, Mizushina Y, Koyama S, Ishikawa Y, Hagiwara K
  • Journal Title: BMC Pulm Med. Volume: 20(1) Issue: 1 Pages: 93-93
  • DOI: 10.1186/s12890-020-1133-y
  • Peer Reviewed / Open Access
• [Journal Article] Impact of DNA integrity on the success rate of tissue‐based next‐generation sequencing: Lessons from nationwide cancer genome screening project SCRUM‐Japan GI‐SCREEN (2020)
  • Author(s): Kuwata Takeshi、Wakabayashi Masashi、Hatanaka Yutaka、Morii Eiichi、Oda Yoshinao、Taguchi Kenichi、Noguchi Masayuki、Ishikawa Yuichi、Nakajima Takashi、Sekine Shigeki、Nomura Shogo、Okamoto Wataru、Fujii Satoshi、Yoshino Takayuki、SCRUM‐Japan GI‐SCREEN Pathology Group
  • Journal Title: Pathology International Volume: 70 Issue: 12 Pages: 932-942
  • DOI: 10.1111/pin.13029
  • NAID: 120007147854
  • Peer Reviewed / Open Access
• [Journal Article] Impact of older age on clinicopathological and prognostic features of colon cancer in postmenopausal women (2020)
  • Author(s): Honma Naoko、Matsuda Yoko、Arai Tomio、Kawachi Hiroshi、Akishima‐Fukasawa Yuri、Yamamoto Noriko、Ueno Masashi、Ishikawa Yuichi、Mikami Tetuo
  • Journal Title: Pathology International Volume: e-pub Issue: 7 Pages: 433-440
  • DOI: 10.1111/pin.12936
  • Peer Reviewed
• [Journal Article] Mucinous lung adenocarcinoma, particularly referring to EGFR‐mutated mucinous adenocarcinoma (2019)
  • Author(s): Wakejima R, Inamura K, Ninomiya H, Nagano H, Mun M, Okumura S, Okubo K, Ishikawa Y.
  • Journal Title: Pathology International Volume: 70 Issue: 2 Pages: 72-83
  • DOI: 10.1111/pin.12879
  • Peer Reviewed