Skip to main content

Advertisement

SpringerLink
Log in

The promoter methylation status of the DNA repair gene O 6-methylguanine-DNA methyltransferase in ulcerative colitis

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Patients with long-standing and extensive ulcerative colitis (UC) have an increased incidence of colorectal cancer (CRC). It has been reported that a DNA repair gene, O 6-methylguanine-DNA methyltransferase (MGMT) is inactivated by promoter hypermethylation in sporadic CRCs. Hence, we investigated the promoter methylation status of MGMT by methylation specific polymerase chain reaction (PCR) in a total of 67 tissue samples (61 non-cancerous tissues and 6 cancer tissues) from 24 patients with UC. Promoter hypermethylation of MGMT was detected in one well-differentiated adenocarcinoma (16.7%) of 6 cancer samples and not detected in any of adenomas and dysplasias. In non-dysplastic tissues, promoter hypermethylation of MGMT was detected in 2 (3.7%, mucosa with mild inflammation) of 54 samples. The frequency of MGMT promoter hypermethylation in UC-associated CRCs found in this study (16.7%) is obviously lower than previously reported in sporadic CRCs (39.0–42.0%). We also confirmed that 42.9% (6/14) of sporadic CRCs showed the promoter methylation. These findings indicated that promoter hypermethylation of the MGMT gene is infrequent in patients with UC, and may not closely contribute to UC-associated colorectal tumorigenesis. A different genetic pathway for tumor progression may exist between sporadic CRC and UC-associated CRC.

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

Fig. 1.

Similar content being viewed by others

References

  1. Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP (1998) Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 58:5489–5494

    CAS  PubMed  Google Scholar 

  2. Aust DE, Willenbucher RF, Terdiman JP, Ferrell LD, Chang CG, Moore DH II, Molinaro-Clark A, Baretton GB, Loehrs U, Waldman FM (2000) Chromosomal alterations in ulcerative colitis-related and sporadic colorectal cancers by comparative genomic hybridization. Hum Pathol 31:109–114

    CAS  PubMed  Google Scholar 

  3. Bell SM, Kelly SA, Hoyle JA, Lewis FA, Taylor GR, Thompson H, Dixon MF, Quirke P (1991) c-Ki-ras gene mutations in dysplasia and carcinomas complicating ulcerative colitis. Br J Cancer 64:174–178

    CAS  PubMed  Google Scholar 

  4. Burmer GC, Levine DS, Kulander BG, Haggitt RC, Rubin CE, Rabinovitch PS (1990) c-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma. Gastroenterology 99:416–420

    CAS  PubMed  Google Scholar 

  5. Chaubert P, Benhattar J, Sarage E, Costa J (1994) K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis. Am J Pathol 144:767–775

    CAS  PubMed  Google Scholar 

  6. Ekbom A (1998) Risk of cancer in ulcerative colitis. J Gastrointest Surg 2:312–313

    Article  CAS  PubMed  Google Scholar 

  7. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    PubMed  Google Scholar 

  8. Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, Herman JG (2000) Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 60:129–133

    CAS  PubMed  Google Scholar 

  9. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG (2000) 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 60:2368–2371

    CAS  PubMed  Google Scholar 

  10. Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229

    CAS  PubMed  Google Scholar 

  11. Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG (2001) 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 61:4689–4692

    CAS  PubMed  Google Scholar 

  12. Herfarth KK, Brent TP, Danam RP, Remack JS, Kodner IJ, Wells SA Jr, Goodfellow PJ (1999) A specific CpG methylation pattern of the MGMT promoter region associated with reduced MGMT expression in primary colorectal cancers. Mol Carcinog 24:90–98

    Article  CAS  PubMed  Google Scholar 

  13. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR. A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826

    Article  CAS  PubMed  Google Scholar 

  14. Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M, Porschen R (1998) Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res 58:3942–3945

    CAS  PubMed  Google Scholar 

  15. Ishitsuka T, Kashiwagi H, Konishi F (2001) Microsatellite instability in inflamed and neoplastic epithelium in ulcerative colitis. J Clin Pathol 54:526–532

    Article  CAS  PubMed  Google Scholar 

  16. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7:536–540

    CAS  PubMed  Google Scholar 

  17. Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61:3573–3577

    CAS  PubMed  Google Scholar 

  18. Kitazawa S, Kitazawa R, Maeda S (2000) Identification of methylated cytosine from archival formalin-fixed paraffin-embedded specimens. Lab Invest 80:275–276

    CAS  PubMed  Google Scholar 

  19. Lennard JJE, Morson BC, Ritchie JK, Shove DC, Williams CB (1977) Cancer in colitis: assessment of the individual risk by clinical and histological criteria. Gastroenterology 73:1280–1289

    Google Scholar 

  20. Lashner BA, Silverstein MD, Hanauer SB (1989) Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci 34:1536–1541

    CAS  PubMed  Google Scholar 

  21. Matts SGF (1961) The value of rectal biopsy in the diagnosis of ulcerative colitis. Quart J Med 30:393–407

    CAS  Google Scholar 

  22. Oue N, Shigeishi H, Kuniyasu H, Yokozaki H, Kuraoka K, Ito R, Yasui W (2001) Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma. Int J Cancer 93:805–809

    CAS  PubMed  Google Scholar 

  23. Pieper RO, Patel S, Ting SA, Futscher BW, Costello JF (1996) Methylation of CpG island transcription factor binding sites is unnecessary for aberrant silencing of the human MGMT gene. J Biol Chem 271:13916–13924

    Article  CAS  PubMed  Google Scholar 

  24. Park TJ, Han SU, Cho YK, Paik WK, Kim YB, Lim IK (2001) Methylation of O (6)-methylguanine-DNA methyltransferase gene is associated significantly with K-ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma. Cancer 92:2760–2768

    Article  CAS  PubMed  Google Scholar 

  25. Riddell RH, Goldman H, Ransohoff DF, Appelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BC (1983) Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 14:931–968

    CAS  PubMed  Google Scholar 

  26. Sato F, Harpaz N, Shibata D, Xu Y, Yin J, Mori Y, Zou TT, Wang S, Desai K, Leytin A, Selaru FM, Abraham JM, Meltzer SJ (2002) Hypermethylation of the p14(ARF) gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res 62:1148–1151

    CAS  PubMed  Google Scholar 

  27. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, Baylin SB, Issa JP (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 59:2307–2312

    CAS  PubMed  Google Scholar 

  28. Umetani N, Sasaki S, Watanabe T, Shinozaki M, Matsuda K, Ishigami H, Ueda E, Muto T (1999) Genetic alterations in ulcerative colitis-associated neoplasia focusing on APC, K-ras gene and microsatellite instability. Jpn J Cancer Res 90:1081–1087

    CAS  PubMed  Google Scholar 

  29. Whitehall VLJ, Walsh MD, Young J, Leggett BA, Jass JR (2001) Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 61:827–830

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Japan

    Shunji Matsumura, Naohide Oue, Reiko Ito, Hirofumi Nakayama & Wataru Yasui

  2. Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, 734-8551, Hiroshima, Japan

    Yasuhiko Kitadai & Kazuaki Chayama

  3. Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Faculty of Medical Sciences, 650-0017, Kobe, Japan

    Hiroshi Yokozaki

Authors
  1. Shunji Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naohide Oue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reiko Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirofumi Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuhiko Kitadai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroshi Yokozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuaki Chayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wataru Yasui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wataru Yasui.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsumura, S., Oue, N., Ito, R. et al. The promoter methylation status of the DNA repair gene O 6-methylguanine-DNA methyltransferase in ulcerative colitis. Virchows Arch 443, 518–523 (2003). https://doi.org/10.1007/s00428-003-0877-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-003-0877-0

Keywords

Search

Navigation