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粘膜上皮恒常性維持の破たんによる腫瘍発生機序のシステム的理解

Publicly Offered Research

Project AreaConquering cancer through neo-dimensional systems understanding
Project/Area Number 16H01569
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Complex systems
Research InstitutionThe University of Tokyo

Principal Investigator

古川 洋一  東京大学, 医科学研究所, 教授 (20272560)

Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywordsゲノム / エピゲノム / トランスクリプトーム
Outline of Annual Research Achievements

平成29年度は、主にPOLEの生殖細胞系列変異によって生じた大腸腫瘍について、ゲノム、エピゲノム、トランスクリプトームデータをもとに統合解析を行った。その結果、同一患者に発生した腫瘍の中でメチル化関連遺伝子に体細胞変異を伴うと、ゲノムワイドなメチル化異常が生じ、腫瘍細胞はCIMP (CpG island methylator phenotype)あるいはMSI (microsatellite instability)となることが示された。したがってPOLE変異が生ずると、複製過程でのプルーフ校正不全により変異が蓄積しやすくなって腫瘍が生じ、その後に獲得するゲノム変異、あるいはエピゲノム変異により、同じ患者に生じた腫瘍でも腫瘍の性格が異なることが明らかとなった。
虫垂原発の腫瘍病変から発生した腹膜偽粘液腫(PMP)の解析では、全ゲノム・トランスクリプトーム解析を実施した。その結果、PMPは通常の大腸がんとは異なる発現プロファイルを持っていた。すなわち、分化した腸吸収細胞で発現するSLC26A3などのマーカーの発現が低下し、盃細胞で発現するTFF3などのマーカーの発現が高いことが確認された。すなわち腫瘍細胞が盃細胞へ分化する細胞から発生したか、腫瘍化したのちに盃細胞への脱分化をおこしたのか2つの可能性が考えられた。発現変化した5176遺伝子を用いたパスウェイ解析の結果では、EMTや炎症関連分子の変化との相関が認められた。全ゲノム解析では、KRAS、GRAS遺伝子の変異の他、TP53、PIK3CA、AKT1遺伝子や、プロテインキナーゼ・シグナルに関わる遺伝子に変異を認めた。これらの結果は、PMPの発生・進展を考えるうえで、有用な情報になるものと期待される。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (22 results)

All 2018 2017 2016

All Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 7 results,  Acknowledgement Compliant: 1 results) Presentation (13 results) (of which Int'l Joint Research: 6 results,  Invited: 9 results)

  • [Journal Article] Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation.2018

    • Author(s)
      Ikenoue T, Terakado Y, Zhu C, Liu X, Ohsugi T, Matsubara D, Fujii T, Kakuta S,Kubo S, Shibata T, Yamaguchi K, Iwakura Y, Furukawa Y.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 2021-2021

    • DOI

      10.1038/s41598-018-19769-1

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex.2017

    • Author(s)
      Zhu C, Yamaguchi K, Osugi T, Terakado Y, Noguchi R, Ikenoue T, Furukawa Y
    • Journal Title

      Cancer Science

      Volume: 印刷中 Issue: 4 Pages: 612-619

    • DOI

      10.1111/cas.13174

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Decreased expression of interferon-induced protein 2 (IFIT2) by Wnt/β-catenin signaling confers anti-apoptotic properties to colorectal cancer cells.2017

    • Author(s)
      Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Furukawa Y.
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 59 Pages: 100176-100186

    • DOI

      10.18632/oncotarget.22122

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic alterations in Japanese extrahepatic biliary tract cancer.2017

    • Author(s)
      Noguchi R, Yamaguchi K, Ikenoue T, Terakado Y, Ohta Y, Yamashita N, Kainuma O, Yokoi S, Maru Y, Nagase H, Furukawa Y.
    • Journal Title

      Oncology Letters

      Volume: 14 Issue: 1 Pages: 877-884

    • DOI

      10.3892/ol.2017.6224

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Requirement of glycosylation machinery in TLR responses revealed by CRISPR/Cas9 screening2017

    • Author(s)
      Sato Ryota、Shibata Takuma、Tanaka Yu、Kato Chiharu、Yamaguchi Kiyoshi、Furukawa Yoichi、Shimizu Eigo、Yamaguchi Rui、Imoto Seiya、Miyano Satoru、Miyake Kensuke
    • Journal Title

      International Immunology

      Volume: 29 Issue: 8 Pages: 347-355

    • DOI

      10.1093/intimm/dxx044

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis2016

    • Author(s)
      Yamaguchi K, Nagayama S, Shimizu E, Komura M, Yamaguchi R, Shibuya T, Arai M, Hatakeyama S, Ikenoue T, Ueno M, Miyano S, Imoto S, Furukawa Y
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 26011-26011

    • DOI

      10.1038/srep26011

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pseudomyxoma peritonei of a mature ovarian teratoma caused by mismatch repair deficiency in a patient with Lynch syndrome: a case report.2016

    • Author(s)
      Gohda Y, Noguchi R, Horie T, Igari T, Nakamura H, Ohta Y, Yamaguchi K, Ikenoue T, Hatakeyama S, Yusa N, Furukawa Y, Yano H
    • Journal Title

      BMC Medical Genetics

      Volume: 17 Issue: 1 Pages: 94-94

    • DOI

      10.1186/s12881-016-0356-5

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aromatase inhibitor efficacy pharmacogenomics and MIR2052HG long noncoding RNA polymorphisms2016

    • Author(s)
      Ingle JN, Xie F, Ellis MJ, Goss PE, Shepherd LE, Chapman J-A W, Chen BE, Kubo M, Furukawa Y, Momozawa Y, Stearns V, Pritchard KI, Barman P, Carlson EE, Goetz MP, Weinshilboum RM, Kalari KR, Wang L
    • Journal Title

      Cancer Research

      Volume: 76 Issue: 23 Pages: 7012-7023

    • DOI

      10.1158/0008-5472.can-16-1371

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.2016

    • Author(s)
      Hertz DL, Owzar K, Lessans S, Wing C, Jiang C, et al.
    • Journal Title

      Clinical Cancer Research

      Volume: 22 Issue: 19 Pages: 4890-4900

    • DOI

      10.1158/1078-0432.ccr-15-2823

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Identification of FERM Domain-Containing Protein 5 (FRMD5) as a Novel Target of β-Catenin/TCF7L2 Complex2017

    • Author(s)
      Furukawa Y, Zhu C, Ohsugi T, Terakado Y, Noguchi R, Ikenoue T, Yamaguchi K,
    • Organizer
      AACR Annual Meeting 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Wnt Signaling Induces Anti-Apoptotic Effect in Colorectal Cancer Cells Through the Suppression of IFITs2017

    • Author(s)
      Ohsugi T, Zhu C, Ohsugi T, Terakado Y, Noguchi R, Ikenoue T, Yamaguchi K, Furukawa Y
    • Organizer
      AACR Annual Meeting 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゲノム情報を用いた治療薬開発・治療法選択2017

    • Author(s)
      古川洋一
    • Organizer
      第26回日本癌病態治療研究会シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 人工知能を用いた臨床シークエンスの取り組み2017

    • Author(s)
      古川洋一
    • Organizer
      第15回日本臨床腫瘍学会学術集会シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 臨床シークエンスにおける人工知能を用いた精密医療開発2017

    • Author(s)
      古川洋一
    • Organizer
      第59回日本小児血液・がん学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 次世代シーケンスがもたらす個別化医療の新時代2017

    • Author(s)
      古川 洋一
    • Organizer
      ポスト京シンポジウム
    • Place of Presentation
      東京 上野国立科学博物館
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 次世代シーケンスがもたらす個別化医療の新時代2017

    • Author(s)
      古川 洋一
    • Organizer
      沖縄県先端医療実用化推進事業シンポジウム
    • Place of Presentation
      沖縄 ロワジールホテル那覇
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Identification of deleterious genetic changes in familial and rare cancers and application of their information for personalized healthcare2017

    • Author(s)
      Furukawa Y
    • Organizer
      2017 International Symposium on Joint Research Project of the Institute of Medical Science
    • Place of Presentation
      東京 東大医科学研究所
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] がん診療へのNGSとIBM Watson の利用2016

    • Author(s)
      古川 洋一
    • Organizer
      CBI学会2016年大会
    • Place of Presentation
      東京 タワーホール船堀
    • Year and Date
      2016-10-25
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] NGSによる家族性大腸がんの原因と病態の解明2016

    • Author(s)
      古川 洋一、山口 貴世志、清水 英悟、上村 光弘、山口 類、渋谷 哲朗、井元 清哉、矢野秀朗、池上 恒雄、宮野 悟
    • Organizer
      第75回日本癌学会シンポジウム
    • Place of Presentation
      横浜 パシフィコ横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Practice of Clinical Sequence for Cancer in IMSUT2016

    • Author(s)
      Furukawa Y
    • Organizer
      The International Workshop on Bioinformatics and Systems Biology 2016
    • Place of Presentation
      東京 東大医科学研究所
    • Year and Date
      2016-08-08
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Genetic alterations identified in the APC gene by the use of NGS for patients with polyposis of the colon2016

    • Author(s)
      Furukawa Y, Komura M, Shimizu E, Yamaguchi R, Shibuya T, Imoto S, Sugimura H, Nagayama S, Yamaguchi K, Ikenoue T, Miyano S
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      京都 京都国際会議場
    • Year and Date
      2016-04-04
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of deleterious changes in familial cancer and application of cancer genome data in clinics2016

    • Author(s)
      Furukawa Y
    • Organizer
      International Symposium in Okinawa, 2016
    • Place of Presentation
      沖縄 パシフィックホテル沖縄
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2016-04-26   Modified: 2019-12-27  

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