Elucidating biological characteristics of DNA repair gene mutations in prostate cancer utilizing cell-free DNA analysis
| Project/Area Number |
20H03814
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 56030:Urology-related
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
|
|---|
| 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)
Research Products
(9 results)
