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Elucidation of new molecular mechanism of cancer caused by gene promoter methylation and its clinical aplication

Research Project

Project/Area Number 14571198
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionOKAYAMA UNIVERSITY

Principal Investigator

MATSUBARA Nagahide  Okayama University, Medical and Dental Hospital, Assistant Professor, 医学部・歯学部附属病院, 助手 (70314672)

Co-Investigator(Kenkyū-buntansha) ISOZAKI Hiroshi  Okayama University, Medical and Dental Hospital, Associate Professor, 医学部・歯学部附属病院, 助教授 (50151436)
TANAKA Noriaki  Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (10127566)
SHIMIZU Kenji  Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (10037286)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥2,100,000 (Direct Cost: ¥2,100,000)
Keywordsgastroenterological cancer / carcinogenesis / genetic alteration / epigenetic alteration / colorectal cancer / gastric cancer / esophageal cancer / microsatellite instability / epigenetics / methylation / promoter / gastrointestinal neoplasia / DNA repair / epitenetics / gastrointestinal neoplasea / repair
Research Abstract

We have been studied molecular mechanisms of gastrointestinal carcinogenesis and cancer progression. One of our research focuses is colorectal cancer, and we have found the cancer specific mutation in E2F4, one of the important transcription factors, as a new gene strongly related to the colorectal cancer progression characterized as microsatellite instability phenotype (published 2 articles in Cancer Res.). We also found ING-1 as a new important target gene in esophageal squamouse cell cancer (published in Cancer Res.). We also studied the molecular events occur in early stages (just invaded into submucosa) of colorectal cancer, and we found high prevalence of microsatellite in low frequency (MSI-L) in this group of cancers (published in Cancer Res. ). Frequency of MSI-L in advanced colorectal cancer is really low around 10%, however, we found MSI-L phenotype in 50% of the early stage colorectal cancers. Now more and more researchers are involved in the new MSI-L carcinogenesis pathwa … More y, which was thought to be an artifact an thus not a meaningful phenomenon.
Recently not only genetic, including mutations and deletions, but also epigenetic phenomenon are involved in many types of carcinogenesis. The most typical epigenetic alteration is the promoter hypermethylation, which causes the silencing of the gene. DNA methylation occurs preferentially within dense clusters of CpG sites know as CpG islands. Therefore reference is made to a CpG island methlator phenotype (CIMP). Most of our recent work was focused on this promoter methylation of multiple genes in gastrointestinal cancers, and we made tremendous progress in this field. We found that the important DNA repair gene MGMT (O6-methylguanine DNA methyltransferase) is controlled of its expression by promoter methylation, by analyzing precise map of methylation in its promoter. We also found that the level of methylation is strongly related to the prognosis and chemoresistance of colorectal cancers (Clinical Cancer Research). Furthermore, we classified colorectal cancer by mutational status of KRAS and BRAF, and showed close correlation to the methylation status of the multiple promoter methylation in colorectal cancer (Journal of Clinical Oncology). Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (36 results)

All 2005 2004 2003 2002 Other

All Journal Article (30 results) Book (1 results) Publications (5 results)

  • [Journal Article] Methylatio profiles of genes utilizing newly developed CpG island methylation2005

    • Author(s)
      Naoki Kimuran et al.
    • Journal Title

      Nucleic Acids Res. 33

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effects of histone deacetylase inhibitor FR901228 on expression level of telome2005

    • Author(s)
      Jun Murakami et al.
    • Journal Title

      Cancer Chemoth.Pharm.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Methylatio profiles of genes utilizing newly developed CpG island methylation microarray on colorectal cancer patients.2005

    • Author(s)
      Naoki Kimura, Takeshi Nagasaka, Jun Murakami, Hiromi Sasamoto, Masahiro Murakami, Noriaki Tanaka, Nagahide Matsubara
    • Journal Title

      Nucleic Acids Res. 33(5)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Allele-specific methylation analysis on upstream promoter region of H 19 by me2004

    • Author(s)
      Hiromi Sasamoto et al.
    • Journal Title

      Int J.Oncol 25

      Pages: 1273-1278

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes show different patterns of DNA methylation.2004

    • Author(s)
      Takeshi Nagasaka, et al.
    • Journal Title

      J.Clin.Oncol. 22

      Pages: 4584-4594

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Diagnostic application of hMLf1 methylation in hereditary non-polyposis colore2004

    • Author(s)
      Nagahide Matsubara
    • Journal Title

      Disease Markers 20

      Pages: 277-282

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Methylation assay by nucleotide incorporation (MANIC) : a novel, nonisotopic, q2004

    • Author(s)
      Takeshi Yamamoto et al.
    • Journal Title

      BioTchniques 36

      Pages: 846-855

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] BRAF mutation is associated with DNA methylation in serrated polyps and canc2004

    • Author(s)
      Takeshi Kambara et al.
    • Journal Title

      Gut 53

      Pages: 1137-1144

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Influence of CpG island methylation status in O6-methylguanine-DNA methyltransferase expression of oral cancer cell lines.2004

    • Author(s)
      Murakami, J., et al.
    • Journal Title

      Oncol.Rep. 12

      Pages: 339-345

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effects of demethylating agent 5-aza-2'-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines.2004

    • Author(s)
      Murakami, J., et al.
    • Journal Title

      Oral Oncol. 40

      Pages: 597-603

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Role of Inherited Defects of MYH in the Development of Sporadic Colorectal Cancer.2004

    • Author(s)
      Takeshi Kambara, et al.
    • Journal Title

      Gene Chromosome Canc. 40

      Pages: 1-9

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Allelic loss of a common microsatellite marker MYCL1 : a useful prognostic factor of poor outcomes in colorectal cancer.2004

    • Author(s)
      Kambara, T., et al.
    • Journal Title

      Clinical Cancer Res. 10

      Pages: 1758-1763

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Hypermethylation of O6-methylguanine-DNA methyltransferase promoter maypredict nonrecurrence after chemotherapy in colorectal cancer cases.2004

    • Author(s)
      Nagasaka, T., et al.
    • Journal Title

      Clinical Cancer Res. 9

      Pages: 5306-5312

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Low-level microsatellite instability in most colorectal carcinomas. Cancer Res., 62:1166-1170, 2002.2004

    • Author(s)
      Jass, J.R., et al.
    • Journal Title

      Cancer Res. 62

      Pages: 5988-5990

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Instabilotyping reveals unique mutational spectra in microsatellite-unstable gastric cancers.2004

    • Author(s)
      Mori, Y., et al.
    • Journal Title

      Cancer Res. 62

      Pages: 3641-3645

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Allelic imbalance and microsatellite instability in plasma DNA released from pol2004

    • Author(s)
      Moriyama, H., et al.
    • Journal Title

      Int J.Oncol 21

      Pages: 949-956

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effects of histone deacetylase inhibitor FR901228 on expression level of telomerase reverse transcriptase in oral cancer.2004

    • Author(s)
      Jun Murakami, Junichi Asaumi, Noriko Kawai, Hidetsugu Tsujigiwa, Yoshinobu Yanagi, Hitoshi Nagatsuka, Tetsuyoshi Inoue, Susumu Kokeguchi, Shoji Kawasaki, Masahiro Kuroda, Noriaki Tanaka, Nagahide Matsubara, Kanji Kishi
    • Journal Title

      Cancer Chemoth. Pharm.

    • NAID

      120002314067

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Allele-specific methylation analysis on upstream promoter region of H19 by methylation-specific PCR with confronting two-pair primers.2004

    • Author(s)
      Hiromi Sasamoto, Takeshi Nagasaka, Kenji Notohara, Kazuo Ozaki, Hiroshi Isozaki, Noriaki Tanaka, Nagahide Matsubara
    • Journal Title

      Int. J. Oncol. 25

      Pages: 1273-1278

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes show different patterns of DNA methylation.2004

    • Author(s)
      Takeshi Nagasaka, Hiromi Sasamoto, Kenji Notohara, Harry M.Cullings, Masanori Takeda, Keigo Kimura, Takeshi Kambara, Donald G.MacPhee, Joanne Young, Barbara A.Leggett, Jeremy R.Jass, Noriaki Tanaka, Nagahide Matsubara
    • Journal Title

      J. Clip. Oncol. 22(22)

      Pages: 4584-4594

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Diagnostic application of hMLH1 methylation in hereditary non-polyposis colorectal cancer.2004

    • Author(s)
      Nagahide Matsubara
    • Journal Title

      Disease Markers 20(4-5)

      Pages: 277-282

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Methylation assay by nucleotide incorporation (MANIC): a novel, nonisotopic, quantitative assay for regional CpG methylation density.2004

    • Author(s)
      Takeshi Yamamoto, Takeshi Nagasaka, Kenji Notohara, Hiromi Sasamoto, Jun Murakami, Noriaki Tanaka, Nagahide Matsubara
    • Journal Title

      Bio Tchniques 36

      Pages: 846-855

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.2004

    • Author(s)
      Takeshi Kambara, Lisa A.Simms, Vicki L.J.Whitehall, Kevin J.Spring, Coral V.A.Wynter, Michael D.Walsh, Melissa A.Barker, Sven Arnold, Andrina McGivern, Nagahide Matsubara, Noriaki Tanaka, Tetsuro Higuclu, Joanne Young, Jeremy R.Jass, Barbara A.Leggett
    • Journal Title

      Gut 53

      Pages: 1137-1144

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Influence of CpG island methylation status in 06-methylguanine-DNA methyltransferase expression of oral cancer cell lines.2004

    • Author(s)
      Murakami, J., Asaumi, J., Maki, Y., Tsujigiwa, H., Nagatsuka, H., Kokeguchi, S., Inoue, T., Kawasaki, S., Tanaka, N., MacPhee, D., Matsubara, N., Kishi, K.
    • Journal Title

      Oncol. Rep. 12

      Pages: 339-45

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effects of demethylating agent 5-aza-2'-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines.2004

    • Author(s)
      Murakami, J., Asaumi, J., Maki, Y., Tsujigiwa, H., Kuroda M., Nagai, N., Yanagi, Y., Inoue, T., Kawasaki, S., Tanaka, N., Matsubara.N., Kishi K.
    • Journal Title

      Oral Oncol. 40

      Pages: 597-603

    • NAID

      120002312161

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Role of Inherited Defects of MYH in the Development of Sporadic Colorectal Cancer.2004

    • Author(s)
      Takeshi Kambara, Vicki L.J.Whitehall, Kevin J.Spring, Melissa A.Barker, Sven Arnold, Coral V.A.Wynter, Nagahide Matsubara, Noriaki Tanaka, Joanne P.Young, Barbara A.Leggett, Jeremy R.Jass
    • Journal Title

      Gene Chromosome Canc. 40

      Pages: 1-9

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Allelic loss of a common microsatellite marker MYcL1: a useful prognostic factor of poor outcomes in colorectal cancer.2004

    • Author(s)
      Kambara, T., Sharp, GB., Nagasaka, T., Takeda, M., Sasamoto, H., Nakagawa, H., Isozaki, H., MacPhee, D.G., Jass, J.R., Tanaka, N., Matsubara, N.
    • Journal Title

      Clinical Cancer Res. 10

      Pages: 1758-1763

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Hypermethylation of 06-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases.2003

    • Author(s)
      Nagasaka, T., Sharp, GB., Notohara, K., Kambara, T., Sasamoto, H., Isozaki, H., MacPhee, D.G., Jass, J.R., Tanaka, N., Matsubara, N.
    • Journal Title

      Clinical Cancer Res. 9

      Pages: 5306-5312

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Low-level microsatellite instability in most colorectal carcinomas. Cancer Res., 62: 1166-1170, 2002.2002

    • Author(s)
      Jass, J.R., Whitehall, V.L.J., Young, J., Leggett, B., Meltzer, S.J., Matsubara.N., Fishel, R.: Correspondence re: P.Laiho, et al.
    • Journal Title

      Cancer Res. 62

      Pages: 5988-5990

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Instabilotyping reveals unique mutational spectra in microsatellite-unstable gastric cancers.2002

    • Author(s)
      Mori, Y., Sato, F., Selaru, F.M., Olaru, A., Perry, K., Kimos, M.C., Tamura, G., Matsubara, N., Wang, S., Xu, Y., Yin, J., Zou, T.T., Leggett, B., Young, J., Nukiwa, T., Stine, O.C., Abraham, J.M., Shibata, D., Meltzer, S.J.
    • Journal Title

      Cancer Res. 62

      Pages: 3641-3645

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Allelic imbalance and microsatellite instability in plasma DNA released from polyclonal pancreatic adenocarcinoma.2002

    • Author(s)
      Moriyama, H., Matsubara, N., Kambara, T., Mori, M., Matsuoka, J., Yoshino, T., Takakura, N., Shimizu, K., Tanaka, N.
    • Journal Title

      Int. J. Oncol. 21

      Pages: 949-956

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Book] メチレーションチップ-プロモーターのメチル化による遣伝子の不活性化を検出するチップ- DNAチッブまるわかり2004

    • Author(s)
      松原長秀, 木村直紀
    • Total Pages
      142
    • Publisher
      羊土社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagasaka, T., Sharp, G.B., Notohara, K., Kambara, T., Sasamoto, H., Isozaki, H., MacPhee, D.G., Jass, J.R., Tanaka, N., Matsubara, N.: "Hypermethylation of 06-methylguanine-DNA methyltransferase promoter may predict nonrecurrence after chemotherapy in colorectal cancer cases"Clinical Cancer Res.. 10. 5306-5312 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kambara, T., Sharp, G.B., Nagasaka, T., Takeda, M., Sasamoto, H., Nakagawa, H., Isozaki, H., MacPhee, D.G., Jass, J.R., Tanaka, N., Matsubara, N: "Allelic loss of a common microsatellite marker MYCL1 : a useful prognostic factor of poor outcomes in colorectal cancer."Clinical Cancer Res.. 10. 1758-1763 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Murakami, J., Asaumi, J., Maki, Y., Tsujigiwa, H., Kuroda M., Nagai, N., Yanagi, Y., Inoue, T., Kawasaki, S., Tanaka, N., Matsubara, N., Kishi K: "Effects of demethylating agent 5-aza-2'-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines."Oral Oncol. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takeshi Yamamoto, Takeshi Nagasaka, Kenji Notohara, Hiromi Sasamoto, Jun Murakami, Noriaki Tanaka, Nagahide Matsubara: "Methylation assay by nucleotide incorporation (MANIC) : a novel, nonisotopic, quantitative assay for regional CpG methylation density."BioTchniques. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagahide Matsubara: "Possible implication of methylation test combined with microsatellite instability or pathological analysis for the effective recruitment of Lynch syndrome."Disease Markers. (In press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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