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Investigation of TERT expression and development of a novel targeted therapy in ependymomas

Research Project

Project/Area Number 16K10775
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurosurgery
Research InstitutionNational Cancer Center Japan

Principal Investigator

ICHIMURA KOICHI  国立研究開発法人国立がん研究センター, 研究所, 分野長 (40231146)

Research Collaborator Takadera Mutsumi  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords上衣腫 / 融合遺伝子 / RELA / TERT / トランスジェニックマウス / マウス脳腫瘍モデル / レンチウイルス / ルシフェラーゼ / rs2853669 / 脳腫瘍 / Ependymoma
Outline of Final Research Achievements

We investigated a large number of surgical ependymoma samples for the presence of RELA-fusion and TERT expression. We found RELA-fusion in the majority of supratentorial ependymomas and elevated TERT expression in all of them. To investigate the mechanism of TERT overexpression, we generated a luciferase construct with TERT promoter mutations or rs2853669 SNP. We found that the transcriptional activity of TERT promoter affected by the mutations or SNP was variable according to the length of the promoter region. In order to make a mouse model of ependymoma, we generated conditional double transgenic mouse by mating Nestin-Cre and Cag-Cas9 mouse and lentivirally introduced a RELA-fusion together with a sgRNA for Cdkn2a into the mouse brain. This resulted in development of mouse brain tumors that histologically resembles human ependymomas.

Academic Significance and Societal Importance of the Research Achievements

本研究では、100例あまりの上衣腫検体においてTERTの発現、プロモーターの点突然変異及びメチル化、TERTコピー数異常、遺伝子再配列に対して詳細な解析を行い、TERT高発現の頻度とその機序を精査した。また、TERT promoter長やその領域の点変異やSNPの有無とTERTの転写活性変化の関連性を検討した。またRELA融合遺伝子の導入によるマウス上衣腫のモデルを作成した。本研究の成果は、マウスモデルを用いたTERT標的治療の効果の検証等による上衣腫に対する新規治療標的探索研究への応用が期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (11 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (7 results) (of which Int'l Joint Research: 3 results,  Invited: 5 results) Remarks (1 results)

  • [Int'l Joint Research] The Hospital for Sick Children(カナダ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Hospital for Sick Children, Toronto(カナダ)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.2018

    • Author(s)
      Fukuoka K, Kanemura Y, Makino K(26番目) et al.
    • Journal Title

      Acta neuropathologica communications

      Volume: 6 Issue: 1 Pages: 134-134

    • DOI

      10.1186/s40478-018-0630-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Molecular classification of supratentorial ependymomas2019

    • Author(s)
      市村幸一
    • Organizer
      The 3rd Ependymoma Consensus Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 遺伝子異常から見た小児脳腫瘍 WHO 分類の光と影2018

    • Author(s)
      市村幸一
    • Organizer
      関東小児脳腫瘍カンファレンス
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] hTERT in glioma - a multifaceted demigod -2017

    • Author(s)
      市村幸一
    • Organizer
      世界脳腫瘍学会(WFNOS2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 成人グリオーマにおけるTERTプロモーター変異の意義2017

    • Author(s)
      市村幸一
    • Organizer
      第18回日本分子脳神経外科学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] hTERT in glioma - a multifaceted demigod -2017

    • Author(s)
      市村幸一
    • Organizer
      COGNO2017 ASM
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Molecular classification of supratentorial and posterior fossa ependymomas2017

    • Author(s)
      市村幸一
    • Organizer
      第59回日本小児血液・がん学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 小児脳腫瘍についてのゲノム研究から明らかになった 新規知見と臨床への展開2016

    • Author(s)
      市村幸一
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
    • Invited
  • [Remarks] 国立がん研究センター研究所 ホームページ

    • URL

      https://www.ncc.go.jp/jp/ri/division/brain_tumor_translational_research/index.html

    • Related Report
      2017 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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