Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Oncogenomics
  • Published:

Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer

Oncogene volume 26, pages 4435–4441 (2007)Cite this article

Abstract

The mutated in colorectal cancer (MCC) gene is in close linkage with the adenomatous polyposis coli (APC) gene on chromosome 5, in a region of frequent loss of heterozygosity in colorectal cancer. The role of MCC in carcinogenesis, however, has not been extensively analysed, and functional studies are emerging, which implicate it as a candidate tumor suppressor gene. The aim of this study was to examine loss of MCC expression due to promoter hypermethylation and its clinicopathologic significance in colorectal cancer. Correspondence of MCC methylation with gene silencing was demonstrated using bisulfite sequencing, reverse transcription–polymerase chain reaction and Western blotting. MCC methylation was detected in 45–52% of 187 primary colorectal cancers. There was a striking association with CDKN2A methylation (P<0.0001), the CpG island methylator phenotype (P<0.0001) and the BRAF V600E mutation (P<0.0001). MCC methylation was also more common (P=0.0084) in serrated polyps than in adenomas. In contrast, there was no association with APC methylation or KRAS mutations. This study demonstrates for the first time that MCC methylation is a frequent change during colorectal carcinogenesis. Furthermore, MCC methylation is significantly associated with a distinct spectrum of precursor lesions, which are suggested to give rise to cancers via the serrated neoplasia pathway.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Ashton-Rickardt PG, Wyllie AH, Bird CC, Dunlop MG, Steel CM, Morris RG et al. (1991). MCC, a candidate familial polyposis gene in 5q21, shows frequent allele loss in colorectal and lung cancer. Oncogene 6: 1881–1886.

    CAS  PubMed  Google Scholar 

  • Bouwmeester T, Bauch A, Ruffner H, Angrand P-O, Bergamini G, Croughton K et al. (2004). A physical and functional map of the human TNF-α/NF-κB signal-transduction pathway. Nat Cell Biol 6: 97–105.

    Article  CAS  PubMed  Google Scholar 

  • Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D et al. (2000). MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28: e32.

    Article  CAS  PubMed  Google Scholar 

  • Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW . (1999). CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59: 2302–2306.

    CAS  PubMed  Google Scholar 

  • Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN et al. (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 

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H et al. (1991). Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589–600.

    Article  CAS  PubMed  Google Scholar 

  • Hawkins NJ, Ward RL . (2001). Sporadic colorectal cancers with microsatellite instability and their possible origin in HP and serrated adenomas. J Natl Cancer Inst 93: 1307–1313.

    Article  CAS  PubMed  Google Scholar 

  • 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 USA 93: 9821–9826.

    Article  CAS  PubMed  Google Scholar 

  • Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T et al. (2003). Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res 63: 8132–8137.

    CAS  PubMed  Google Scholar 

  • Jass JR, Iino H, Ruszkiewicz A, Painter D, Solomon MJ, Koorey DJ et al. (2000). Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 47: 43–49.

    Article  CAS  PubMed  Google Scholar 

  • Jass JR . (2005). Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract Oncol 2: 398–405.

    Article  CAS  PubMed  Google Scholar 

  • Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD et al. (2004). BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53: 1137–1144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karin M, Cao Y, Greten FR, Li Z-W . (2002). NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2: 301–310.

    Article  CAS  PubMed  Google Scholar 

  • Kinzler KW, Nilbert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ et al. (1991). Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251: 1366–1370.

    Article  CAS  PubMed  Google Scholar 

  • Kohonen-Corish MRJ, Daniel JJ, Chan C, Lin BP, Kwun SY, Dent OF et al. (2005). Low microsatellite instability is associated with poor prognosis in stage C colon cancer. J Clin Oncol 23: 2318–2324.

    Article  CAS  PubMed  Google Scholar 

  • Matsumine A, Senda T, Baeg GH, Roy BC, Nakamura Y, Noda M et al. (1996). MCC, a cytoplasmic protein that blocks cell cycle progression from the G0/G1 to S-phase. J Biol Chem 271: 10341–10346.

    Article  CAS  PubMed  Google Scholar 

  • Nagasaka T, Sasamoto H, Notohara K, Cullings HM, Takeda M, Kimura K et al. (2004). Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol 22: 4584–4594.

    Article  CAS  PubMed  Google Scholar 

  • Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A et al. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 252: 665–669.

    Article  Google Scholar 

  • O'Brien MJ, Yang S, Clebanoff JL, Mulcahy E, Farraye FA, Amorosino M et al. (2004). Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28: 423–434.

    Article  PubMed  Google Scholar 

  • Rashid A, Shen L, Morris JS, Issa JP, Hamilton SR . (2001). CpG island methylation in colorectal adenomas. Am J Pathol 159: 1129–1135.

    Article  CAS  PubMed  Google Scholar 

  • Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA et al. (2005a). Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129: 837–845.

    Article  CAS  PubMed  Google Scholar 

  • Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA et al. (2005b). Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65: 6063–6070.

    Article  CAS  PubMed  Google Scholar 

  • Senda T, Matsumine A, Yanai H, Akiyama T . (1999). Localization of MCC (mutated in colorectal cancer) in various tissues of mice and its involvement in cell differentiation. J Histochem Cytochem 47: 1149–1157.

    Article  CAS  PubMed  Google Scholar 

  • Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP . (1999). CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96: 8681–8686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al. (1988). Genetic alterations during colorectal-tumor development. New Engl J Med 319: 525–532.

    Article  CAS  PubMed  Google Scholar 

  • Ward RL, Cheong K, Ku SL, Meagher A, O'Connor T, Hawkins NJ . (2003). Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21: 3729–3736.

    Article  CAS  PubMed  Google Scholar 

  • Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al. (2006). CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38: 787–793.

    Article  CAS  PubMed  Google Scholar 

  • Wynter CVA, Walsh MD, Higuchi T, Leggett BA, Young J, Jass JR . (2004). Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Gut 53: 573–580.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Cancer Institute NSW, the Australian Cancer Research Foundation and the Strathfield Private Hospital for financial support and Francis Lam for providing the frozen tumor specimens. Jawad Saab, Joseph Daniel, Nicola Currey, Ron Buttenshaw, Daniel Buchanan, Hoey Koh and Lisa Simms provided expert technical assistance.

Author information

Authors and Affiliations

  1. Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    M R J Kohonen-Corish, N D Sigglekow, J Susanto, T J Seng & R L Sutherland

  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales, Australia

    M R J Kohonen-Corish & R L Sutherland

  3. Department of Colorectal Surgery, Concord Hospital and University of Sydney, Sydney, Australia

    P H Chapuis, E L Bokey & O F Dent

  4. Department of Anatomical Pathology, Concord Hospital and University of Sydney, Sydney, Australia

    C Chan & B P C Lin

  5. USC/Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    P W Laird

  6. Molecular Cancer Epidemiology Laboratory, QIMR, Herston, Australia

    J Young

  7. Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation and Queensland Institute of Medical Research, Brisbane, Australia

    B A Leggett

  8. Department of Pathology, McGill University, Montreal, Canada

    J R Jass

Authors
  1. M R J Kohonen-Corish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N D Sigglekow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Susanto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P H Chapuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E L Bokey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O F Dent
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B P C Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. T J Seng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P W Laird
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. B A Leggett
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J R Jass
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R L Sutherland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M R J Kohonen-Corish.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kohonen-Corish, M., Sigglekow, N., Susanto, J. et al. Promoter methylation of the mutated in colorectal cancer gene is a frequent early event in colorectal cancer. Oncogene 26, 4435–4441 (2007). https://doi.org/10.1038/sj.onc.1210210

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210210

Keywords

This article is cited by

Search

Advanced search

Quick links