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Identification of novel driver genes by whole genome sequencing of early stage lung tumors

Research Project

Project/Area Number 20H00545
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research InstitutionNational Cancer Center Japan

Principal Investigator

Kohno Takashi  国立研究開発法人国立がん研究センター, 研究所, 分野長 (80280783)

Co-Investigator(Kenkyū-buntansha) 鈴木 絢子  東京大学, 大学院新領域創成科学研究科, 准教授 (00770348)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥44,980,000 (Direct Cost: ¥34,600,000、Indirect Cost: ¥10,380,000)
Fiscal Year 2023: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
Fiscal Year 2021: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
Fiscal Year 2020: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
Keywords肺がん / ゲノム / 遺伝子 / 治療標的 / 癌 / 遺伝学 / 病理学
Outline of Research at the Start

喫煙者を主体とした欧米肺がんのゲノム解析が大規模に進むものの、遺伝子変化の多様さから、新規ドライバー遺伝子の同定は滞っている。申請者は、欧米症例と比べ遺伝子変異数が1/10レベルと少ない肺発がん初期病変の外科的手術摘出標本の凍結サンプルや非喫煙者腺がんを多数所有している。また、RET点変異など新たな候補ドライバー変化を本サンプルで予備的に同定している。そこで本課題では、長鎖全ゲノム・エピゲノムシークエンス等を含めた先駆的な全ゲノムシークエンス解析をこれらの検体に対して行い、新規ドライバー遺伝子変化やその治療的意義を解明するとともに、ドライバー遺伝子変化を介さない肺発がん機構の特徴を解明する。

Outline of Final Research Achievements

Based on genomic alterations in adenocarcinoma in situ and minimally invasive adenocarcinoma, the mechanism of early lung carcinogenesis was clarified (Haga et al, Nat Comm, 2023). Oncogene alterations were found to function in the formation of early lung tumors, and mutations in cancer suppressor genes were found to function in the malignant transformation of early tumors. Global DNA hypomethylation and associated copy number changes and large-scale structural changes were inferred to contribute to malignant transformation. Novel oncogenic mutations were found among RET gene mutations, and their activation and oncogenic potential were demonstrated to be suppressed by RET kinase inhibitors. In conclusion, point mutations in the RET gene contribute to carcinogenesis of multiple cancer types, including lung cancer, and are therapeutic target molecules.

Academic Significance and Societal Importance of the Research Achievements

世界的にも貴重な上皮内肺がん、微小浸潤腺がんのゲノム変化を明らかにすることで、これまで明らかにされていなかった早期肺腫瘍形成の分子機構が明らかになり、その成果を国際一流紙に報告することができた。この知見は今後の肺がん予防や早期発見・治療のための基盤情報となると期待される。また、がん遺伝子変化陰性例にみられるRET遺伝子変異が、がん原性変異であり、既存RET阻害薬の治療標的となることが明らかにされた。今後、コンパニオン検査への本情報の組み込みなどがんゲノム医療への実装が望まれる。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Comments on the Screening Results   Annual Research Report
  • Research Products

    (38 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (7 results) Journal Article (15 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 15 results,  Open Access: 9 results) Presentation (13 results) (of which Int'l Joint Research: 2 results,  Invited: 9 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Crick Institute(英国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] NCI(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] トロント大学(カナダ)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Crick研究所(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] NCI(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] The CRICK Institute(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] NCI, NIH(米国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Passive Smoking?Induced Mutagenesis as a Promoter of Lung Carcinogenesis2024

    • Author(s)
      Mochizuki Akifumi、Shiraishi Kouya、Honda Takayuki、Higashiyama Ryoko Inaba、Sunami Kuniko、Matsuda Maiko、Shimada Yoko、Miyazaki Yasunari、Yoshida Yukihiro、Watanabe Shun-Ichi、Yatabe Yasushi、Hamamoto Ryuji、Kohno Takashi
    • Journal Title

      Journal of Thoracic Oncology

      Volume: in press Issue: 7 Pages: 984-994

    • DOI

      10.1016/j.jtho.2024.02.006

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma2023

    • Author(s)
      Haga Y, Sakamoto Y, Kajiya K, Kawai H, Oka M, Motoi N, Shirasawa M, Yotsukura M, Watanabe S, Arai M, Zenkoh J, Shiraishi K, Seki M, Kanai A, Shiraishi Y, Yatabe Y, Matsubara D, Suzuki Y, Noguchi M, Kohno T, Suzuki A.
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 8375-8375

    • DOI

      10.1038/s41467-023-43732-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinicopathological characteristics and molecular analysis of lung cancer associated with ciliated muconodular papillary tumor/bronchiolar adenoma2023

    • Author(s)
      Higashiyama Masahiro、Motoi Noriko、Yotsukura Masaya、Yoshida Yukihiro、Nakagawa Kazuo、Yagishita Shigehiro、Shirasawa Masayuki、Yoshida Tatsuya、Shiraishi Kouya、Kohno Takashi、Ohe Yuichiro、Watanabe Shun‐ichi
    • Journal Title

      Pathology International

      Volume: 73 Issue: 5 Pages: 188-197

    • DOI

      10.1111/pin.13316

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis2022

    • Author(s)
      Tabata Junya、Nakaoku Takashi、Araki Mitsugu、Yoshino Ryunosuke、Kohsaka Shinji、Otsuka Ayaka、Ikegami Masachika、Ui Ayako、Kanno Shin-ichiro、Miyoshi Keiko、Matsumoto Shigeyuki、Sagae Yukari、Yasui Akira、Sekijima Masakazu、Mano Hiroyuki、Okuno Yasushi、Okamoto Aikou、Kohno Takashi
    • Journal Title

      Cancer Research

      Volume: 82 Issue: 20 Pages: 3751-3762

    • DOI

      10.1158/0008-5472.can-22-0834

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-Term Prognosis and Prognostic Indicators of Stage IA Lung Adenocarcinoma2022

    • Author(s)
      Yotsukura Masaya、Muraoka Yuji、Yoshida Yukihiro、Nakagawa Kazuo、Shiraishi Kouya、Kohno Takashi、Yatabe Yasushi、Watanabe Shun-ichi
    • Journal Title

      Annals of Surgical Oncology

      Volume: 30 Issue: 2 Pages: 851-858

    • DOI

      10.1245/s10434-022-12621-x

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phasing analysis of lung cancer genomes using a long read sequencer2022

    • Author(s)
      Sakamoto Yoshitaka、Miyake Shuhei、Oka Miho、Kanai Akinori、Kawai Yosuke、Nagasawa Satoi、Shiraishi Yuichi、Tokunaga Katsushi、Kohno Takashi、Seki Masahide、Suzuki Yutaka、Suzuki Ayako
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 3464-3464

    • DOI

      10.1038/s41467-022-31133-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Accounting for EGFR mutations in epidemiological analyses of non-small cell lung cancers: Examples based on the International Lung Cancer Consortium data2022

    • Author(s)
      Schmid S, Jiang M, Brown MC, Fares A, Garcia M, Soriano J, Dong M, Thomas S, Kohno T, etal.
    • Journal Title

      Cancer Epidemiol Biomarkers Prev

      Volume: 31 Issue: 3 Pages: 679-687

    • DOI

      10.1158/1055-9965.epi-21-0747

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients2021

    • Author(s)
      Jiang Mei、Fares Aline F.、Shepshelovich Daniel、Yang Ping、Christiani David、Zhang Jie、Shiraishi Kouya、et al
    • Journal Title

      Lung Cancer

      Volume: 152 Pages: 58-65

    • DOI

      10.1016/j.lungcan.2020.11.029

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma2021

    • Author(s)
      Shirasawa Masayuki、Yoshida Tatsuya、Takayanagi Daisuke、Shiraishi Kouya、Yagishita Shigehiro、Sekine Katsutoshi、Kanda Shintaro、Matsumoto Yuji、Masuda Ken、Shinno Yuki、Okuma Yusuke、Goto Yasushi、Horinouchi Hidehito、Hamada Akinobu、Kohno Takashi、Yamamoto Noboru、Watanabe Shun-ichi、Ohe Yuichiro、Motoi Noriko
    • Journal Title

      Clinical Lung Cancer

      Volume: 22 Issue: 4 Pages: 282-291

    • DOI

      10.1016/j.cllc.2021.02.003

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long-term prognosis of patients with resected adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung.2021

    • Author(s)
      Yotsukura M, Asamura H, Motoi N, Kashima J, Yoshida Y, Nakagawa K, Shiraishi K, Kohno T, Yatabe Y, Watanabe SI.
    • Journal Title

      J Thorac Oncol

      Volume: 16 Issue: 8 Pages: 1312-1320

    • DOI

      10.1016/j.jtho.2021.04.007

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC2021

    • Author(s)
      Shirasawa M, Yoshida T, Shimoda Y, Takayanagi D, Shiraishi K, Kubo T, Mitani S, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Ichikawa H, Kohno T, Yamamoto N, Matsumoto S, Goto K, Watanabe SI, Ohe Y, Motoi N.
    • Journal Title

      J Thorac Oncol

      Volume: 16 Issue: 1 Pages: 2078-2090

    • DOI

      10.1038/s41598-021-98527-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer2021

    • Author(s)
      Ishioka Kota、Yasuda Hiroyuki、Hamamoto Junko、Terai Hideki、Emoto Katsura、Kim Tae-Jung、Hirose Shigemichi、Kamatani Takashi、Mimaki Sachiyo、Arai Daisuke、Ohgino Keiko、Tani Tetsuo、Masuzawa Keita、et al
    • Journal Title

      Cancer Research

      Volume: 81 Issue: 14 Pages: 3916-3929

    • DOI

      10.1158/0008-5472.can-20-4048

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants2021

    • Author(s)
      Arakawa A, Ichikawa H, Kubo T, Motoi N, Kumamoto T, Nakajima M, Yonemori K, Noguchi E, Sunami K, Shiraishi K, Kakishima H, Yoshida H, Hishiki T, Kawakubo N, Kuroda T, Kiyokawa T, Yamada K, Yanaihara N, et al, and Kohno T, Ogawa C.
    • Journal Title

      New England Journal of Medicine

      Volume: 384 Issue: 1 Pages: 42-50

    • DOI

      10.1056/nejmoa2030391

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative'-type lung adenocarcinomas.2021

    • Author(s)
      Hamada K, Tian Y, Fujimoto M, Takahashi Y, Kohno T, Tsuta K, Watanabe SI, Yoshida T, Asamura H, Kanai Y, Arai E.
    • Journal Title

      Carcinogenesis

      Volume: 42 Issue: 2 Pages: 169-179

    • DOI

      10.1093/carcin/bgaa115

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-read sequencing for non-small-cell lung cancer genomes2020

    • Author(s)
      Sakamoto Y, Xu L, Seki M, Yokoyama TT, Kasahara M, Kashima Y, Ohashi A, Shimada Y, Motoi N, Tsuchihara K, Kobayashi SS, Kohno T, Shiraishi Y, Suzuki A, Suzuki Y.
    • Journal Title

      Genome Res

      Volume: 30 Issue: 9 Pages: 1243-57

    • DOI

      10.1101/gr.261941.120

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Lung cancer medicine and prevention utilizing germline information2023

    • Author(s)
      Kohno T
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Drug susceptibility model for RET resistance mutations through combined in vitro and in silico analyses2023

    • Author(s)
      Nakaoku T, Maruyama K, Nukaga S, Kohno T.
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Development of a 3D-structure-based drug response model to help annotating kinase mutations for precision medicine2023

    • Author(s)
      Maruyama K, Nakaoku T, Nukaga S, Kohno T
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Development of a 3D-structure-based drug response model to help annotating kinase mutations for precision medicine2023

    • Author(s)
      Maruyama K, Nakaoku T, Araki M, Nukaga S, Okuno Y, Kohno T
    • Organizer
      CBI学会2023年大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Whole genome sequencing-based precision cancer medicine in Japan2023

    • Author(s)
      Kohno T
    • Organizer
      第20回日本臨床腫瘍学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 長鎖シークエンス技術を用いた非小細胞肺がんオミクス解析2023

    • Author(s)
      鈴木絢子
    • Organizer
      令和4年度国際がん研究シンポジウム
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ロングリード全ゲノムシークエンスとフェーズ情報解析による肺がんゲノム変異パターンの解明2022

    • Author(s)
      鈴木絢子、坂本祥駿、鈴木穣
    • Organizer
      第81回日本肺癌学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 非喫煙者肺がん・喫煙者肺がんの病因とゲノム解析2022

    • Author(s)
      河野隆志
    • Organizer
      第 116 回日本肺癌学会 関西支部学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 肺がんと遺伝子、わかったこと、わからないこと2021

    • Author(s)
      河野隆志
    • Organizer
      第62回日本肺癌学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ロングリードシークエンス技術を駆使した早期および進行肺がんの比較全ゲノム解析2021

    • Author(s)
      鈴木絢子
    • Organizer
      第62回日本肺癌学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Molecular Epidemiology of Asian Lung Cancer2020

    • Author(s)
      Takashi Kohno, Kouya Shiraishi, Takashi Nakaoku
    • Organizer
      IASLC 2020 WCLC World Conference on Lung Cancer
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Targeting RET-VUS in precision oncology using molecular dynamics simulation2020

    • Author(s)
      Takashi Nakaoku, Junya Tabata, Mitsugu Araki, Yasushi Okuno, Takashi Kohno
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] The Landscape of oncogenic function of RET tyrosine kinase2020

    • Author(s)
      Junya Tabata, Takashi Nakaoku, Takashi Kohno
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Remarks] 1-2 早期肺発がん機構の研究

    • URL

      https://www.ncc.go.jp/jp/ri/division/genome_biology/project/010/20170906193233.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 最適化がん治療の研究

    • URL

      https://www.ncc.go.jp/jp/ri/division/genome_biology/project/020/20190125.html

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report 2020 Annual Research Report
  • [Patent(Industrial Property Rights)] RETキナーゼ阻害剤によるがん治療の有効性を判定する方法2022

    • Inventor(s)
      河野隆志、中奥敬史
    • Industrial Property Rights Holder
      河野隆志、中奥敬史
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2022-089905
    • Filing Date
      2022
    • Related Report
      2022 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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