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Role of the c-kit tyrosine kinase in the genesis of gastrointestinal stromal tumors.

Research Project

Project/Area Number 09671305
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionOsaka University

Principal Investigator

NISHIDA Toshirou  Osaka University Medical School, Assistant Professor, 医学部, 助手 (40263264)

Co-Investigator(Kenkyū-buntansha) HIROTA Seiichi  Osaka University Medical School, Associate Professor, 医学部, 助教授 (50218856)
UCHIYAMA Yasuo  Osaka University Medical School, Professor, 医学部, 教授 (10049091)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordsgastrointestinal tract / proto-oncogene / gain-of-function mutation / stromal tumors / recurrence / prognosis / c-kit / 消化管平滑筋腫 / Interstitial Cells Cajal / 再発
Research Abstract

The etiology and cellular origin of gastrointestinal stroma tumors (GISTs) are unknown.Sequencing of c-kil complementary DNA from five GISTs revealed mutations in the juxtamembrane domain.All corresponding mutant KIT proteins were constitutively activated without KIT ligand, the stem cell factor (SCF).Stable transfection of the mutant c-kil complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells.Because the development of the interstitial cells of Cajal (ICCs) is dependent on the SCF-KlT interaction and because both GISTs and ICCs express KIT and CD 34, GISTs may originate from the ICCs.We have found a family with multiple GISTs, of which many family members suffered from multiple GISTs and related symptoms.The family members with multiple GISTs showed the same c-kil mutation in the juxtamembrance domain.The c-kil mutation of this family was detected not only in GISTs but also in leukocytes, thus, familial GISTs appeared to be a cancer syndrome.Next we examined the correlation between the presence of c-kil mutation and the prognosis of GISTs.One hundred and twenty four patients with GIST were analyzed.Most GISTs (89%) express the c-kil protein, and missense mutations of exon 11 were found in 71 out of 124 GISTs.These 71 mutation-positive (+) GISTs were larger in size and invaded more frequently to adjacent tissues compared with the 53 mutation-negative (-) GISTs.Histologically, the mutation (+) GISTs showed higher mitotic figures and more necrosis and hemorrhage.The patients with mutation (+) GISTs showed more frequent recurrences and higher mortality than those with mutation (-) GISTs.The c-kil mutation was an independent prognostic factor for overall and cause-specific survival of the patients with GISTs.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Hirota S.et al.: "Gain-of-function mutation of c-kit in human gastrointestinal stromal tumors." Science. 279. 577-580 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishida T.et al.: "Familial Gastrointestinal Stromal Tumors with Germ Line Mutation of the KTT gene." Nature Genetics. 19. 323-324 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakahara M.et al.: "A nobel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors." Gastroenterology. 115. 1090-1095 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kitamura Y.et al.: "Molecular Pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors." Ann.Chir.Gyn.(in press.). (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishida T.et al.: "Endothelin A receptor blockade worsens endotoxin induced hepatic microcirculatory changes and necrosis." Gastroenterology. 115. 412-420 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishida T.et al.: "Prognostic Significance of Proliferative Cell Nuclear Antigen in Carcinoma of the Extrahepatic Bile Duct." World J Surg. 21. 634-639 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirota S,Isozaki K,Moriyama Y,Kanakura Y,Nishida T,et al.: "Gain-of-function mutation of c-kit in human gastrointestinal stromal tumors." Science. 279. 577-580 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishida T,Hirota S,Taniguchi M,Hashimoto K,et al.: "Familial Gastrointestinal Stromal Tumors with Germ Line Mutation of the KIT gene." Nature Genetics. 19. 323-324 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nakahara M,Isozaki K,Hirata S,Taniguchi M,Nishida T,et al.: "A nobel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors." Gastroenterology. 115. 1090-1095 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kitamura Y,Hirota S,Nishida T.: "Molecular Pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors." Ann.Chir.Gyn.(in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishida T,Huang T,Seiyama A,Hamada E,Kamiike W,et al.: "Endothelin A receptor blockade worsens endotoxin induced hepatic microcirculatory changes and necrosis." Gastroenterology. 115. 412-420 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nishida T,Nakao K,Hamaji M,Nakahara M,Tsujimoto M.: "Prognostic Significance of Proliferative Cell Nuclear Antigen in Carcinoma of the Extrahepatic Bile Duct." World J Surg. 21. 634-639 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirota S.et al.: "Gain-of-function mutation of c-kit in human gastrointestinal stromal tumors." Science. 279. 577-580 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishida T.et al.: "Familial Gastrointestinal Stromal Tumors with Germ Line Mutation of the KIT gene." Nature Genetics. 19. 323-324 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nakahara M.et al.: "A nobel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors." Gastroenterology. 115. 1090-1095 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kitamura Y.et al.: "Molecular Pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors." Ann.Chir.Gyn.(in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishida T.et al.: "Endothelin A receptor blockade worsens endotoxin induced hepatic microcirculatory changes and necrosis." Gastroenterology. 115. 412-420 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishida T.et al.: "Prognostic Significance of Proliferative Cell Nuclear Antigen in Carcinoma of the Extrahepatic Bile Duct." World J Surg. 21. 634-639 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hirota S.et al.: "Gain-of-function mutation of c-kit in human gastrointestinal stromal tumors." Science. 279. 577-580 (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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