Investigation of mechanism of bladder cancer formation by molecular analysis of field change bladder urothelium.

• Project/Area Number: 20K18139
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Osaka University
• Principal Investigator: Hayashi Yujiro 大阪大学, 医学系研究科, 招へい教員 (20804412)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 遺伝子変異 / 膀胱癌 / 発癌 / field change / 腫瘍形成 / 早期診断 / TERT promoter / 正常粘膜 / Field change

Outline of Research at the Start

我が国の筋層非浸潤性膀胱癌患者数は再発率が高いため膀胱鏡など侵襲的で費用のかかる検査を繰り返し必要とする。そこで我々は非悪性尿路上皮に存在し発癌に関連するField changeに注目した網羅的遺伝子発現解析による膀胱癌再発メカニズムを解明し、これらの情報を基に新規膀胱癌再発リスク分類を作成するとともに、尿中cell-free DNAによる高精度かつ低侵襲な術後経過観察を実現することを本研究の目的とする。

Outline of Final Research Achievements

In bladder cancer, driver mutations are reported to exist as field changes in the mucosa without pathological evidence of malignancy, and are likely to be associated with tumor recurrence and bladder cancer development, but the molecular biological mechanism of field changes has not been elucidated. In this study, we performed a comprehensive gene mutation analysis of the normal bladder mucosa to elucidate the mechanism of bladder cancer recurrence.
Mutational analysis of bladder normal mucosa collected from bladder cancer patients revealed TERT promoter, FGFR3, and CDKN2A mutations, all of which were identified in normal urothelium and are likely to be driver mutations in the genome evolution of bladder cancer.

Academic Significance and Societal Importance of the Research Achievements

これまで明らかになっていなかった筋層非浸潤性膀胱癌の腫瘍形成に関わる遺伝子変異を同定できた。筋層非浸潤性膀胱癌と筋層浸潤性膀胱癌では異なる遺伝子プロファイルを持つ可能性が示唆され、治療法を考える上で異なるアプローチが必要となる可能性が示唆され、社会的意義は大きいと考えられる。

Research Products

• [Journal Article] Clinical Application of TERT Promoter Mutations in Urothelial Carcinoma (2021)
  • Author(s): Hayashi Yujiro、Fujita Kazutoshi、Netto George J.、Nonomura Norio
  • Journal Title: Frontiers in Oncology Volume: 11
  • DOI: 10.3389/fonc.2021.705440
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TERT C228T mutation in non‐malignant bladder urothelium is associated with intravesical recurrence for patients with non‐muscle invasive bladder cancer (2020)
  • Author(s): Hayashi Yujiro、Fujita Kazutoshi、Nojima Satoshi、Tomiyama Eisuke、Matsushita Makoto、Koh Yoko、Nakano Kosuke、Wang Cong、Ishizuya Yu、Kato Taigo、Hatano Koji、Kawashima Atsunari、Ujike Takeshi、Uemura Motohide、Imamura Ryoichi、Morii Eiichi、Nonomura Norio
  • Journal Title: Molecular Oncology Volume: 14 Issue: 10 Pages: 2375-2383
  • DOI: 10.1002/1878-0261.12746
  • Peer Reviewed / Open Access
• [Presentation] TERT PROMOTER MUTATION IN NON-MALIGNANT UROTHELIUM OF BLADDER IS ASSOCIATED WITH RECURRENCE IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CARCINOMA (2020)
  • Author(s): Yujiro Hayashi*, Kazutoshi Fujita, Kyosuke Matsuzaki, Makoto Matsushita, Yoko Koh, Kosuke Nakano, Cong Wang, Yu Ishizuya, Yoshiyuki Yamamoto, Taigo Kato, Koji Hatano, Atsunari Kawashima, Takeshi Ujike, Motohide Uemura, George Netto, Norio Nonomura
  • Organizer: American Urological Association annual meeting 2020
  • Int'l Joint Research