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Elucidating biological characteristics of DNA repair gene mutations in prostate cancer utilizing cell-free DNA analysis

Research Project

Project/Area Number 20H03814
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56030:Urology-related
Research InstitutionKyoto University

Principal Investigator

Akamatsu Shusuke  京都大学, 医学研究科, 准教授 (20767248)

Co-Investigator(Kenkyū-buntansha) 澤田 篤郎  京都大学, 医学研究科, 講師 (10784796)
小川 修  京都大学, 医学研究科, 名誉教授 (90260611)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2022: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2020: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Keywords去勢抵抗性前立腺癌 / 血中遊離DNA / 相同組み換え修復関連遺伝子 / DNA修復遺伝子 / BRCA / ATM / CDK12 / 前立腺癌 / cfDNA / 経時的DNA解析 / BRCA paradox / 相同組み換え遺伝子異常 / 血中遊離DNA解析
Outline of Research at the Start

我々が独自に開発した血中遊離DNA(cfDNA)の高感度捕捉法により前立腺癌の治療中に蓄積する遺伝子異常を経時的に捕捉し、その遺伝子背景を細胞株で反映することで臨床を模倣するモデルを樹立できると考える。本研究では約100例の臨床検体の経時的cfDNA解析と、臨床検体と遺伝子背景が揃ったモデルを樹立・解析することにより、HDR関連遺伝子異常と病態並びに薬剤感受性の関係を調べ、病態解明を目指す共に、薬剤選択、投薬時期に関するエビデンスを患者毎に創出する。

Outline of Final Research Achievements

We analyzed 100 cases of cell-free DNA (cfDNA) derived from patients with castration-resistant prostate cancer by using our innovative technique, eVIDENCE, an analytic pipeline specifically designed for the detection of circulating tumor DNA (ctDNA) using molecular barcodes. The results showed that deleterious ATM, BRCA2, and TP53 variants were identified even in cases with less than 2% ctDNA fraction, and that these genetic abnormalities are prognostic factors, suggesting the importance of detecting low-frequency variants in cfDNA.
We also generated cell lines to replicate DNA repair gene abnormalities, however, their proliferation was suppressed in contrast to clinical behavior. This phenomenon, BRCA paradox, could not be solved. Nevertheless, we successfully established patient-derived xenografts using specimens obtained from patients with DNA repair gene mutations, which mirrored clinical behavior and allowed interrogation of novel therapeutic targets using pre-clinical models.

Academic Significance and Societal Importance of the Research Achievements

本研究で去勢抵抗性前立腺癌(CRPC)患者由来cfDNAにおける低頻度変異検出の臨床的有用性を示したことで、現行のがんゲノム医療においてcfDNA検査を行う場合に低頻度変異にも着目すべきことが判明し、より多くの患者ががんゲノム医療で恩恵を受けられることがわかった。
さらにCRPCのDNA修復遺伝子異常を反映した細胞株、患者由来ゼノグラフトを作成した。世界的にも貴重な実験系であり、DNA修復遺伝子異常の中でもPARP阻害薬に抵抗性を示すATMやCDK12変異前立腺癌の治療開発への応用が期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (9 results)

All 2023 2021 2020

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (8 results)

  • [Journal Article] Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer2021

    • Author(s)
      Kei Mizuno
    • Journal Title

      Clinical Cancer Research

      Volume: 28 Issue: 22 Pages: 6164-6173

    • DOI

      10.1158/1078-0432.ccr-21-2328

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 去勢抵抗性前立腺癌患者由来cell-free DNAの経時的解析2023

    • Author(s)
      水野桂、赤松秀輔
    • Organizer
      第7回Liquid Biopsy研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] The combination of CDK12 KO and TP53 KD may not mimic aggressive phenotype seen in clinical CDK12 LOF prostate cancer.2021

    • Author(s)
      上山 裕樹
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] CDK12KO前立腺癌細胞株は増殖能低下を示す2021

    • Author(s)
      上山 裕樹
    • Organizer
      第109回 日本泌尿器科学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Frequency of cancer-predisposing genes in advance Japanese prostate cancer patients and their clinical implications2021

    • Author(s)
      木村 博子
    • Organizer
      第109回 日本泌尿器科学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] eVIDENCE を用いた去勢抵抗性前立腺癌患者由来 cell-free DNA の解析2021

    • Author(s)
      水野 桂
    • Organizer
      第30回泌尿器科分子細胞研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Genomic landscape of metastatic hormone-naive prostate cancer2020

    • Author(s)
      水野 桂
    • Organizer
      第79回 日本癌学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] CDK12 null prostate cancer cell line LNCaP shows reduced growth potential2020

    • Author(s)
      上山 裕樹
    • Organizer
      第79回 日本癌学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Analysis of genetic rare variants in Japanese advanced prostate cancer patients.2020

    • Author(s)
      木村 博子
    • Organizer
      第79回 日本癌学会総会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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