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Aberrant methylation of inflammatory bowel disease and its application to risk assessment of cancer

Research Project

Project/Area Number 13670538
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionSapporo Medical University

Principal Investigator

TOYOTA Minoru  Sapporo Medical University, Sch.of Med., Instructor, 医学部, 助手 (70270676)

Co-Investigator(Kenkyū-buntansha) IMAI Kohzoh  Sapporo Medical University, Sch.of Med., Professor, 医学部, 教授 (60117603)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsDNA methylations / Epigenetics / inflammatory bowel disease / Tumor marker / MCA / 分子マーカー / 癌抑制遺伝子 / 炎症 / 前癌病変 / アポトーシス
Research Abstract

CpG island hypermethylation is a mechanism of gene silencing that can be usurped by neoplastic cells to inactivate undesirable genes. In the colon, hypermethylation often starts in normal mucosa as a function of age and is markedly increased in cancer. To test the hypothesis that subjects at increased risk of colon cancer have higher levels of methylation in their nonneoplastic mucosa, we studied methylation patterns of five genes in the normal and dysplastic mucosa of patients with ulcerative colitis (UC), a condition associated with a marked increased risk of colon cancer. One gene (MIh1) was unmethylated in all tissues examined. All four remaining genes had low but detectable levels of methylation in the epithelium of UC patients without evidence of dysplasia, and this methylation was not different from non-UC controls. By contrast, all four genes were highly methylated in dysplastic epithelium from high-grade dysplasia (HGD)/cancer patients with UC ; methylation in HGD versus controls averaged 40.0% versus 7.4% (P=0.00003) for ER, 44.0% versus 3.0% (P<0.00003) for MYOD, 9.4% versus 2.4% (P=0.03) for p16 exon 1, and 57.5% versus 30.6% (P=0.01) for CSPG2. Importantly, three of the four genes were also highly methylated in the normal appearing (nondysplastic) epithelium from these same HGD/cancer patients, indicating that methylation precedes dysplasia and is widespread in these patients. Compared with controls, methylation averaged 20.1% versus 7.2% (P=0.07) for ER, 18.4% versus 3.0% (P<0.008) for MYOD, and 7.9% versus 2.4% (P=0.007) for p16 exon 1. These results are consistent with the hypothesis that age-related methylation marks (and may lead to) the field defect that reflects acquired predisposition to colorectal neoplasia. Furthermore, the data suggest that chronic inflammation is associated with high levels of methylation, perhaps as a result of increased cell turnover, and that UC can be viewed as resulting in premature aging of colorectal epithelial cells.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Shen L: "DNA methylation in human hepatocellular carcinoma is related to environmental exposures"J. Natl Cancer Inst.. 94巻・10号. 755-761 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suh ER: "DNA methylation dowuregulates CDX1 gene expression in colorectal cancer cell lines"J. Biol. Chem.. 277巻・39号. 35795-35800 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kikuchi T: "Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer"Int. J. Cancer. 97巻・3号. 272-277 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kikuchi T: "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors"Oncogene. 27巻・17号. 2741-2749 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogi K: "Aberrant methylation of multiple genes and clinicopathological features of oral squamous cell carcinoma"Clin Cancer Res.. 8巻・10号. 3164-3171 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Issa JP: "Accelerated age-related CpG island methylation in ulcerative colitis"Cancer Res. 61巻・9号. 3573-3577 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shen L: "DNA methylation in human hepatocellular carcinoma is related to environmental exposures"J.Natl.Cancer Inst.. Vol 94(10). 755-761 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suh ER: "DNA methylation downregulates CDX1 gene expression in colorectal cancer cell lines"J.Biol.Chem.. Vol 277(39). 35795-3580 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kikuchi T: "Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer"Int.J.Cancer. Vol 97(3). 272-277 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kikuchi T: "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors"Oncogene. Vol 27(17). 2741-2749 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ogi K: "Aberrant methylation of multiple genes and clinicopathological features of oral squamous cell carcinoma"Clin Cancer Res. Vol 8(10). 3164-3171 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Issa JP: "Accelerated age-related CpG island methylation in ulcerative colitis"Cancer Res. Vol 61(9). 3573-3577 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shen L, Toyota M, Ahuja N, Rashid A, Issa JP.: "DNA methylation in human hepatocellular carcinoma is related to environmental exposures"J. Natl Cancer Inst.. 94巻・10号. 755-761 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suh ER, Toyota M., Traber PG.: "DNA methylation downregulates CDXl gene expression in colorectal cancer cell lines"J. Biol. Chem.. 277巻・39号. 35795-3580 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kikuchi T, Itoh F, Toyota M, Suzuki H, Yamamoto H, Hosokawa M, Imai K.: "Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer"Int. J. Cancer. 97巻・3号. 272-277 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kikuchi T, Toyota M, Itoh F, Suzuki H, Obata T, Kakiuchi H, Kusano M, et al.: "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors"Oncogene. 27巻・17号. 2741-2749 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ogi K, Toyota M, Tanaka N, Kohama G, Tokino T.: "Aberrant methylation of multiple genes and clinicopathological features of oral squamous cell carcinoma"Clin Cancer Res.. 8巻・10号. 3164-3171 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA.: "Accelerated age-related CpG island methylation in ulcerative colitis"Cancer Res. 61巻・9号. 3573-3577 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kikuchi T.: "Aberrant Methylation and Histone Deacethylation of Cyclooxy-genase 2 in Gastric Cancer"Int. J. Cancer. 97. 272-277 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kikuchi T.: "Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacethylation in human tumors"Oncogene. 21(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shen L.: "DNA methylation in human hepatocellular carcinoma is related to environmental exposures"J. Natl. Cancer Inst.. 94(in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Issa JP.: "Accelerated age-related CpG island methylation in ulcerative colitis"Cancer Res.. 61. 3573-3481 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toyota M.: "Methylation profiling in acute myeloid leukemia"Blood. 97. 2823-2829 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ueki T.: "Identification and characterization of differentially methylated CpG islands in pancreatic carcinoma"Cancer Res.. 61. 8540-8546 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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