Skip to main content
SpringerLink
Log in

DNA methylation changes in gastrointestinal disease

  • Gastroenterology and genetics—polymorphic gene and disease-caused gene
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

DNA methylation of the 5′ region of genes is often associated with gene silencing in X-chromosome inactivation and imprinting. Recent studies have indicated that altered DNA methylation plays a role in the inactivation of multiple tumor suppressor genes and DNA repair genes such as pl6INK4A and hMLHl. Colorectal adenomas have a relatively high frequency of methylation, and aberrant methylation is an early event during tumorigenesis. In aging patients, even colon epithelium which appears to be normal showed a significant amount of methylation in a subset of the genes. Colon mucosa from patients with inflammatory bowel disease also showed a high level of methylation. DNA methylation can be a specific diagnostic marker in gastrointestinal cancer and inflammatory bowel disease, for which there is no perfect marker for a noninvasive diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159–70.

    Article  PubMed  CAS  Google Scholar 

  2. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999;21:163–7.

    Article  PubMed  CAS  Google Scholar 

  3. Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 2001;10:687–92.

    Article  PubMed  CAS  Google Scholar 

  4. Toyota M, Itoh F, Imai K. DNA methylation and gastrointestinal malignancies: functional consequences and clinical implications. J Gastroenterol 2000;35:727–34.

    Article  PubMed  CAS  Google Scholar 

  5. Toyota M, Issa JP. CpG island methylator phenotypes in aging and cancer. Semin Cancer Biol 1999;9:349–57.

    Article  PubMed  CAS  Google Scholar 

  6. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature 1998;395:89–93.

    Article  PubMed  CAS  Google Scholar 

  7. Lengauer C, Kinzler KW, Vogelstein B. DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sei USA 1997;94:2545–50.

    Article  CAS  Google Scholar 

  8. Kikuchi T, Toyota M, Itoh F, Suzuki H, Obata T, Yamamoto H, et al. Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors. Oncogene 2002;21:in press.

  9. Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Hinoda Y, et al. Distinct methylation pattern and microsatellite instability in sporadic gastric cancer. Int J Cancer 1999;83:309–13.

    Article  PubMed  CAS  Google Scholar 

  10. Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Imai K. Inactivation of the 14-3-3 sigma gene is associated with 5′ CpG island hypermethylation in human cancers. Cancer Res 2000;60: 4353–7.

    PubMed  CAS  Google Scholar 

  11. Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res 2000;60:1835–9.

    PubMed  CAS  Google Scholar 

  12. Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 1999;59:5438–42.

    PubMed  CAS  Google Scholar 

  13. Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, et al. Hypermethylation-associated inactivation of pl4(ARF) is independent of pl6(INK4a) methylation and p53 mutational status. Cancer Res 2000;60:129–33.

    PubMed  CAS  Google Scholar 

  14. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 2000;60:2368–71.

    PubMed  CAS  Google Scholar 

  15. Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, et al. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G: C to A: T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 2001;61:4689–92.

    PubMed  CAS  Google Scholar 

  16. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994;7:536–40.

    Article  PubMed  CAS  Google Scholar 

  17. Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001;61:3225–9.

    PubMed  CAS  Google Scholar 

  18. Myohanen SK, Baylin SB, Herman JG. Hypermethylation can selectively silence individual pl6ink4A alleles in neoplasia. Cancer Res 1998;58:591–3.

    PubMed  CAS  Google Scholar 

  19. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sei USA 1999;96:8681–6.

    Article  CAS  Google Scholar 

  20. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 1999;59:2307–12.

    PubMed  CAS  Google Scholar 

  21. Toyota M, Ho C, Ohe-Toyota M, Bay lin SB, Issa JP. Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5′ CpG island in human tumors. Cancer Res 1999;59:4535–41.

    PubMed  CAS  Google Scholar 

  22. Toyota M, Shen L, Ohe-Toyota M, Hamilton SR, Sinicrope FA, Issa JP. Aberrant methylation of the cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res 2000;60:4044–8.

    PubMed  CAS  Google Scholar 

  23. Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 1999;59:2302–6.

    PubMed  CAS  Google Scholar 

  24. Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 2000;404:1003–7.

    Article  PubMed  CAS  Google Scholar 

  25. Toyota M, Ohe-Toyota M, Ahuja N, Issa JP. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natal Acad Sei USA 2000;97:710–5.

    Article  CAS  Google Scholar 

  26. Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP. Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 1998; 58:5489–94.

    PubMed  CAS  Google Scholar 

  27. Nakajima T, Akiyama Y, Shiraishi J, Arai T, Yanagisawa Y, Ara M, et al. Age-related hypermethylation of the hMLHl promoter in gastric cancers. Int J Cancer 2001;94:208–ll.

    Article  PubMed  CAS  Google Scholar 

  28. Harpaz N, Talbot IC. Colorectal cancer in idiopathic inflammatory bowel disease. Semin Diagn Pathol 1996;13:339–57.

    PubMed  CAS  Google Scholar 

  29. Brentnall TA, Crispin DA, Rabinovitch PS, Haggitt RC, Rubin CE, Stevens AC, et al. Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 1994;107:369–78.

    PubMed  CAS  Google Scholar 

  30. Rabinovitch PS, Dziadon S, Brentnall TA, Emond MJ, Crispin DA, Haggitt RC, et al. Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. Cancer Res 1999; 59:5148–53.

    PubMed  CAS  Google Scholar 

  31. Tanaka T, Iwasa Y, Kondo S, Hiai H, Toyokuni S. High incidence of allelic loss on chromosome 5 and inactivation of pl5INK4B and pl6INK4A tumor suppressor genes in oxystress-induced renal cell carcinoma of rats. Oncogene 1999;18:3793–7.

    Article  PubMed  CAS  Google Scholar 

  32. Cerda S, Weitzman SA. Influence of oxygen radical injury on DNA methylation. Mutat Res 1997;386:141–52.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan

    Minoru Toyota, Fumio Itoh, Takefumi Kikuchi, Ayumi Satoh, Toshiro Obata, Hiromu Suzuki, Suguru Ishii, Takao Endo & Kohzoh Imai

  2. Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan

    Minoru Toyota & Takashi Tokino

Authors
  1. Minoru Toyota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fumio Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takefumi Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ayumi Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toshiro Obata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiromu Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Suguru Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takao Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takashi Tokino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kohzoh Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Toyota, M., Itoh, F., Kikuchi, T. et al. DNA methylation changes in gastrointestinal disease. J Gastroenterol 37 (Suppl 14), 97–101 (2002). https://doi.org/10.1007/BF03326425

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03326425

Keywords

Search

Navigation