Search for the unique carcinogenic mechanisms of lung cancer with interstitial pneumonia

• Project/Area Number: 19K17669
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Honda Takayuki 東京医科歯科大学, 東京医科歯科大学病院, 助教 (30827259)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 肺がん / 遺伝子変異 / 間質性肺炎 / 発がん / 肺発がん / ゲノム解析 / NKX2-1 / 肺癌

Outline of Research at the Start

間質性肺炎(IP)は肺がん患者の5.8-15.2%に合併し、IPの存在により肺癌発症が10倍となるため発がん母地と考えられてきた。進行期IPに合併した肺がんは進行性かつ治療抵抗性を示すため、新しい診断・治療法の開発が急務である。先行研究でIP合併肺腺がんが通常の浸潤性肺腺がんとは異なりドライバー遺伝子非依存的であることを明らかなったが、IPからどのようにして発がんに至るのか不明である。本研究はこの点を明らかにすべく正常肺胞上皮、IP部、腫瘍部の3領域間での網羅的ゲノム解析・遺伝子発現解析を行い腫瘍形成の経時的変化に伴うゲノム・遺伝子の変化を明らかにする。

Outline of Final Research Achievements

Driver oncogene-independent oncogenic mechanism of lung cancer associated with interstitial pneumonia (IP) was analyzed using whole genome sequencing. Lineage specific gene, NKX2-1, was identified as frequently mutated gene including structural variant in this tumor. These gene aberrations associated with lower expression level of this gene. Target sequencing using surgically resected lung lobe showed accumulation of cancer associated gene mutations in non-cancerous area. These results would be a basis for potentially novel lung carcinogenesis independent from driver oncogene aberrations.

Academic Significance and Societal Importance of the Research Achievements

通常型肺癌と比較して予後不良である間質性肺炎(IP)合併肺癌であるが、既存のドライバー遺伝子の異常では説明できない特徴的な発がん関連遺伝子を有することが明らかになった。これまで研究対象として捉えられることが少なかった肺癌において、その発がん機構の解明に繋がる基礎データが得られ、かつそれは既存の分子標的薬が存在せず、新たな標的遺伝子候補とも考えられた。

Research Products

• [Journal Article] Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy (2021)
  • Author(s): Murakami Naoya、Asami Yuka、Yoshida Hiroshi、Takayanagi Daisuke、Hirose Sou、Kuno Ikumi、Takahashi Kazuaki、Matsuda Maiko、Shimada Yoko、Yamano Shotaro、Sunami Kuniko、Honda Takayuki、Nakahara Tomomi、Watanabe Tomoko、Okuma Kae、Kuroda Takafumi、Kohno Takashi、Kato Tomoyasu、Shiraishi Kouya、Itami Jun
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 10567-10567
  • DOI: 10.1038/s41598-021-90139-0
• [Journal Article] Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease (2021)
  • Author(s): Tasaka Yuri、Honda Takayuki、Nishiyama Naoki、Miyazaki Yasunari、et al.
  • Journal Title: Lung Cancer Volume: 155 Pages: 120-126
  • DOI: 10.1016/j.lungcan.2021.03.014
• [Journal Article] Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women (2020)
  • Author(s): Wong JYY, Zhang H, Hsiung CA, Goto A, et al.
  • Journal Title: Genomics Volume: 112 Issue: 2 Pages: 1223-1232
  • DOI: 10.1016/j.ygeno.2019.07.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simple prediction model for homologous recombination deficiency in breast cancers in adolescents and young adults. (2020)
  • Author(s): Watanabe T, Honda T, Totsuka H, Yoshida M, Tanioka M, Shiraishi K, Shimada Y, Arai E, Ushiama M, Tamura K, Yoshida T, Kanai Y, Kohno T.
  • Journal Title: Breast Cancer Res Treat Volume: 182 Issue: 2 Pages: 491-502
  • DOI: 10.1007/s10549-020-05716-0
  • Peer Reviewed
• [Journal Article] Disruption in the balance between apolipoprotein A-I and mast cell chymase in chronic hypersensitivity pneumonitis. (2020)
  • Author(s): Yukihisa Inoue, Tsukasa Okamoto, Takayuki Honda, Yoshihisa Nukui, Takumi Akashi, Tamiko Takemura, Minoru Tozuka, Yasunari Miyazaki
  • Journal Title: Immunity, inflammation and disease Volume: 8 Issue: 4 Pages: 659-671
  • DOI: 10.1002/iid3.355
  • Peer Reviewed
• [Journal Article] The Utility of Ground-Glass Attenuation Score for Anticancer Treatment-Related Acute Exacerbation of Interstitial Lung Disease Among Lung Cancer Patients With Interstitial Lung Disease (2020)
  • Author(s): Naoki Nishiyama, Takayuki Honda, Manabu Sema, Tatsuo Kawahara, Yasuto Jin, Ichiro Natsume, Tomoshige Chiaki, Takaaki Yamashita, Yoshikazu Tsukada, Reiko Taki, Yoshihiro Miyashita, Kazuhito Saito, Tomoya Tateishi, Hiroyuki Sakashita, Yasunari Miyazaki
  • Journal Title: International Journal of Clinical Oncology Volume: 25 Issue: 2 Pages: 282-291
  • DOI: 10.1007/s10147-019-01576-x
  • Peer Reviewed
• [Journal Article] Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients (2020)
  • Author(s): Hirose S, Murakami N, Takahashi K, Kuno I, Takayanagi D, Asami Y, Matsuda M, Shimada Y, Yamano S, Sunami K, Yoshida K, Honda T, Nakahara T, Watanabe T, Komatsu M, Hamamoto R, Kato MK, Matsumoto K, Okuma K, Kuroda T, Okamoto A, Itami J, Kohno T, Kato T, Shiraishi K, Yoshida H
  • Journal Title: Gynecologic Oncology Volume: 156 Issue: 1 Pages: 203-210
  • DOI: 10.1016/j.ygyno.2019.10.022
  • Peer Reviewed
• [Presentation] Incidence of thromboembolism in lung cancer patients treated with immune checkpoint inhibitors and chemotherapy (2021)
  • Author(s): Satoshi Endo, Tatsuo Kawahara, Takayuki Honda, Yasunari Miyazaki, et al.
  • Organizer: the Asian Pacific Society of Respirology
  • Int'l Joint Research
• [Presentation] Identification of prognostic and therapeutic biomarker of tumor immune-micro-environment infiltrating lymphocytes INOF malignant pleural mesothelioma: A spatial analysis in Asian population (2021)
  • Author(s): Yuting Yin, Rie Sakakibara, Takayuki Honda, Yasunari Miyazaki, et al
  • Organizer: the Asian Pacific Society of Respirology
  • Int'l Joint Research
• [Presentation] Tumor immune-microenvironment of Malignant Pleural Mesothelioma (2021)
  • Author(s): Yuting Yin, Rie Sakakibara, Takayuki Honda, Yasunari Miyazaki, et al
  • Organizer: The 62nd Annual Meeting of Japan Lung Cancer Society
• [Presentation] Distribution of Tumor Mutation Burden in Lung Adenocarcinoma Patients with Usual Interstitial Pneumonia (2019)
  • Author(s): Honda T, Sakashita H, Masai K, Motoi M, Kobayashi M, Akashi T, Mimaki S, Tsuchihara K, Shiraishi K, Okubo K, Watanabe S, Tsuta K, Inase N, Miyazaki Y, Kohno T
  • Organizer: The 59th Annual Meeting of The Japanese Respiratory Society