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Integrated mutation analysis in colorectal cancer

Research Project

Project/Area Number 08407037
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionThe University of Tokyo

Principal Investigator

KITAYAMA Joji (1999)  Dept. Surgery, Faculty of Medicine, University of Tokyo, Associate Professor, 医学部・附属病院, 講師 (20251308)

武藤 徹一郎 (1996-1998)  東京大学, 医学部・附属病院, 教授 (20110695)

Co-Investigator(Kenkyū-buntansha) TSURUO Takashi  Dept. Surgery, Faculty of Medicine, University of Tokyo, Professor, 分子生物学研究所, 教授 (00012667)
NAGAWA Hirokazu  Dept. Surgery, Faculty of Medicine, University of Tokyo, Professor, 医学部・附属病院, 教授 (80228064)
MUTO Tetuichiro  Dept. Surgery, Faculty of Medicine, University of Tokyo, Professor, 医学部・附属病院, 教授 (20110695)
富永 治  東京大学, 医学部・附属病院, 助手 (10261976)
Project Period (FY) 1996 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥37,600,000 (Direct Cost: ¥37,600,000)
Fiscal Year 1999: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1998: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1997: ¥8,500,000 (Direct Cost: ¥8,500,000)
Fiscal Year 1996: ¥16,600,000 (Direct Cost: ¥16,600,000)
KeywordsColorectal cancer / Gene mutation / APC / RAS / BCL-2 / BCL-XL / Chemotherapy / P53 / p21 / BCC-XC / APC遺伝子 / replication error / 放射線治療 / アポトーシス / 細胞周期 / 癌抑制遺伝子 / P53 / Bcl-2 / Dihydropyrimidine dehydrogenase / Apoptosis / Cyclin / DCC
Research Abstract

Recent studies have shown that many genetic changes such as apc, ras, p53 and microsattelite instability, were involved in the development of colorectal cancers. We analyzed those genetic mutations in many clinical samples resected in our institute, and examined the mechanisms of colorectal cancer, and apotosis mechanisms and radiochemosensitivity.
1. In "so called" non-polypoid cancer ; DNA from 63 adenomas (31 polypoid, 17 superficial elevated, 15 superficial depressed), 66 sm carcinomas (47 polypoid, 19non-polypoid) and 34 advance carcinomas were examined for K-ras codon 12 point mutations and APC mutations in the mutation cluster region. K-ras mutation : The frequency in superficial depressed adenomas was lower than that in polypoid adenomas (0% vs. 31% : p=0.018). The frequency in non-polypoid carcinomas was lower than that in polypoid carcinomas (11% vs. 56% : p=0.0008), and was relatively low compared with that in polypoid adenomas (11% vs. 31%). The frequency in superficial depressed adenomas was lower than that in polypoid adenomas (7% vs. 43% : p=0.016), and that in polypoid carcinomas was similar to that in non-polypoid carcinomas. In this non-polypoid pathway, APC mutation seems to be requisite, but K-ras mutation not. It is possible that new APC mutations are acquired after the development of superficial depressed adenomas.
2. Transfection of antisense of Bcl-XL, but not of Bcl-2, significantly increased the sensitivity to 5-Fu in colorectal cancer cells. This indicates suppression of apotosis through Bcl-XL is critically involved in the effects of 5-Fu.
3. P53 and p21 were examined in surgical specimens of rectal cancers immunohistocchemically. The expression of p21, but not of p53, was sell correlated with the sensitivity of preoperative irradiation. This supports the effectiveness of the radiation therapy with p21 positive advanced rectal cancers.

Report

(5 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] 名川弘一(他): "大腸がんの分子生物学"癌と化学療法. 26(14). 2147-2153 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fa. CG etal: "Role 6b P53 and P21/WAF1 detection in patient selection for preperative radiotherapy in colorectal patient"Dis. Colon. Rectum. 41. 08-74 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nita. ME et al: "5Fu induces apoptosis inhuman colon cancer cell lines modulation at BCL-2 proteines"Br. J. Cancer. 78(8). 986-992 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kitaycmd J et al: "Laminine mediates tethering and spreading of colon cancer cells"Br. J. Cancer. 80(12). 1927-1934 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Umetani et al: "Involvement sb Atcand Kras mutation in non-polypoid colorectal tumorigenesis"Br. J. Cancer. 82. 9-15 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sacaki et al: "Microsatellite instability is associated with macroscopic configuration of neoplasm in patients with multiple colerectc Adema"Jap. J. Cein .Oncol. 28. 427-430 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 名川弘一(他): "外科分子病態学"多段階発癌機構. 25 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 名川弘一(他): "大腸の臨床分子病理学"大腸発癌と遺伝子異常. 5 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nagawa H, Muto T: "Molecular biology in colorectal cancer. (Japanese)"Cancer and Chemotherapy. 26(14). 2147-2153 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fu CG, Tominaga O, Nagawa H, Nita ME, Masaki T, Ishimaru G, Higuchi Y, Tsuruo T, Muto T: "Role of p53 and p21/WAF1 detection in patient selection for preoperative"Dis Colon Rectum. 41. 68-74 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nita ME, Nagawa H, Tominaga O, Tsuno N, Fujii S, Fu CG, Takenoue T, Tsuruo T, Muto T: "5-fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins."British Journal of Cancer. 78(8). 986-992 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kitayama J, Nagawa H, Tsuno N, Osada T, Hatano K, Sunami E, Saito H, Muto T: "Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow."Br J Cancer. 80(12). 1927-1934 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Umetani N, Sasaki S, Masaki T, Watanabe T, Matsuda K, Muto T: "Involvement of APC and K-ras mutation in non-polypoid colorectal tumorigenesis."Br. J. Cancer. 82. 9-15 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sasaki S, Masaki T, Umetani N, Shinozaki M, Yokoyama T, Ono M, Nagawa H, Muto T: "Micirosatellite instability is associated with the macroscopic configuration of neoplasms in patients with multiple colorectal adenomas."Jpn J Clin Oncol. 28. 427-430 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nagawa H: "Multiple Steps of colorectal carcinogenesis. (Japanese)"Surgical Molocular Biology. 270-295 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nagawa H, Muto T: "Genetic mutation and colorectal carcinogenesis. (Japanese)"Clinical Molocular Pathology. 100-105 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tominaga O, Nita ME, Nagawa H, Muto T: "Screening for APC mutations based on detection of truncated APC proteins" Digestive Diseases and Science. 43・2. 306-310 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fu CG, Tominaga O, Nagawa H, Turuo T, Muto T: "Role of p53 and p21/WAF1 detection in patient selection for preoperative radiotherapy in rectal cancer patients" Diseases of the Colon and Rectum. 41・1. 68-74 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nita ME, Nagawa H, Tominaga O, Tsuruo T, Muto T: "5-Fluorouracil induces apoptosis in human colon cancer coll lines with modulation of Bcl-2 family proteins" British Journal of Cancer. 78・8. 986-992 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sasaki S, Nagawa H, Muto T: "Microsatellite instability is associated with the macroscopic configuration of neoplasms in patients with multiple colorectal adenomas" Japanese Journal of Clinical Oncology. 28・7. 427-430 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nita M.E.: "Alterations of cell cycle and apoptosis regulators in esophageal and colorectal cancer cell lines." Recent Advances in Gastroenterological Carcinogenesis. I. 439-443 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tominaga O.: "Expressions of cell cycle regulators in human colorectal cancer cell lines." Japanese Journal of Cancer Research. 88. 855-860 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] FuC.G.: "Role of p53,p21/WAF1 detection in patient selection for preoperative radiotherapy in rectal cancer patients." Disease of Colon Rectum. 41. 68-74 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tominaga O.: "Screening for APC mutations based on the detection of truncated APC proteins." Digestive Diseases and Sciences. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Tominaga O.: "Quantification and characterization of total cellular p53 protein in colorectal cancer." Cytometry. 31. 60-66 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nita M.E.: "Dihydropyimidine dehydrogenase but not thymidylate synthase expression is associated with resistance to 5-fluorouracil in colorectal cancer." Hepato-Gastroenterology. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Nita M.E.et al.: "Alterations of cell cycle and apoptosis regulators in esophageal and calorectal cancer cell lines." Recent Advances in Gastroenterological Carcinogenesis. 1. 439-443 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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