CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer (original) (raw)

Nature Genetics volume 38, pages 787–793 (2006)Cite this article

Abstract

Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'1,2. However, the existence of CIMP has been challenged3,4. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAFmutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl. Acad. Sci. USA 96, 8681–8686 (1999).
    Article CAS Google Scholar
  2. Issa, J.P. CpG island methylator phenotype in cancer. Nat. Rev. Cancer 4, 988–993 (2004).
    Article CAS Google Scholar
  3. Yamashita, K., Dai, T., Dai, Y., Yamamoto, F. & Perucho, M. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4, 121–131 (2003).
    Article CAS Google Scholar
  4. Anacleto, C. et al. Colorectal cancer “methylator phenotype”: fact or artifact? Neoplasia 7, 331–335 (2005).
    Article CAS Google Scholar
  5. Samowitz, W.S. et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129, 837–845 (2005).
    Article CAS Google Scholar
  6. Laird, P.W. Cancer epigenetics. Hum. Mol. Genet. 14 Spec No 1, R65–76 (2005).
    Article CAS Google Scholar
  7. Kaufman, L. & Rousseeuw, P.J. Finding Groups in Data: an Introduction to Cluster Analysis (Wiley Interscience, New York, 1990).
    Book Google Scholar
  8. McLachlan, G. & Peel, D. Finite Mixture Models (John Wiley & Sons, New York, 2000).
  9. Kambara, T. et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53, 1137–1144 (2004).
    Article CAS Google Scholar
  10. Toyota, M., Ohe-Toyota, M., Ahuja, N. & Issa, J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc. Natl. Acad. Sci. USA 97, 710–715 (2000).
    Article CAS Google Scholar
  11. Bakin, A.V. & Curran, T. Role of DNA 5-methylcytosine transferase in cell transformation by fos. Science 283, 387–390 (1999).
    Article CAS Google Scholar
  12. Ordway, J.M., Williams, K. & Curran, T. Transcription repression in oncogenic transformation: common targets of epigenetic repression in cells transformed by Fos, Ras or Dnmt1. Oncogene 23, 3737–3748 (2004).
    Article CAS Google Scholar
  13. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215 (1988).
    Article CAS Google Scholar
  14. Whitehall, V.L. et al. Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res. 62, 6011–6014 (2002).
    CAS Google Scholar
  15. Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5, 875–885 (2004).
    Article CAS Google Scholar
  16. Young, J. et al. Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer. Clin. Gastroenterol. Hepatol. 3, 254–263 (2005).
    Article CAS Google Scholar
  17. Young, J. et al. Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am. J. Pathol. 159, 2107–2116 (2001).
    Article CAS Google Scholar
  18. Weisenberger, D.J. et al. Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res. 33, 6823–6836 (2005).
    Article CAS Google Scholar
  19. Eads, C.A. et al. MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res. 28, E32 (2000).
    Article CAS Google Scholar
  20. Eads, C.A. et al. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res. 61, 3410–3418 (2001).
    CAS Google Scholar
  21. Widschwendter, M. et al. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res. 64, 3807–3813 (2004).
    Article CAS Google Scholar
  22. Breiman, L., Friedman, J.H., Olshen, R.A. & Stone, C.J. Classification and Regression Trees 1st edn. (Wadsworth, Belmont, California, 1984).
  23. Hastie, T. et al. 'Gene shaving' as a method for identifying distinct sets of genes with similar expression patterns. Genome Biol. 1, RESEARCH0003.1–RESEARCH0003.21 (2000).
    Article Google Scholar
  24. Herman, J.G., Graff, J.R., Myohanen, S., Nelkin, B.D. & Baylin, S.B. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl. Acad. Sci. USA 93, 9821–9826 (1996).
    Article CAS Google Scholar

Download references

Acknowledgements

The work described in this manuscript was supported by US National Institutes of Health grant R01 CA075090 awarded to P.W.L.

Author information

Author notes

  1. Daniel J Weisenberger and Kimberly D Siegmund: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Surgery and of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, 90089-9176, California, USA
    Daniel J Weisenberger, Mihaela Campan, Tiffany I Long, Mark A Faasse, Deborah Weener, Myungjin Kim & Peter W Laird
  2. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, 90089-9176, California, USA
    Kimberly D Siegmund, Joan Levine & Robert Haile
  3. Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Herston, 4006, Queensland, Australia
    Joanne Young, Daniel Buchanan & Melissa Barker
  4. Department of Pathology, Seoul National University Hospital, Seoul, 110-744, Korea
    Gyeong Hoon Kang
  5. Department of Gynaecological Oncology, Institute for Women's Health, University College London, London, WC1E 6DH, UK
    Martin Widschwendter
  6. Conjoint Gastroenterology Laboratory, Royal Brisbane & Women's Hospital Research Foundation, Clinical Research Centre, Herston, 4006, Queensland, Australia
    Hoey Koh, Lisa Simms & Barbara Leggett
  7. Departments of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, 55905, Minnesota, USA
    Amy J French & Stephen N Thibodeau
  8. Department of Pathology, McGill University, Montreal, H3A 2B4, QC, Canada
    Jeremy Jass

Authors

  1. Daniel J Weisenberger
    You can also search for this author inPubMed Google Scholar
  2. Kimberly D Siegmund
    You can also search for this author inPubMed Google Scholar
  3. Mihaela Campan
    You can also search for this author inPubMed Google Scholar
  4. Joanne Young
    You can also search for this author inPubMed Google Scholar
  5. Tiffany I Long
    You can also search for this author inPubMed Google Scholar
  6. Mark A Faasse
    You can also search for this author inPubMed Google Scholar
  7. Gyeong Hoon Kang
    You can also search for this author inPubMed Google Scholar
  8. Martin Widschwendter
    You can also search for this author inPubMed Google Scholar
  9. Deborah Weener
    You can also search for this author inPubMed Google Scholar
  10. Daniel Buchanan
    You can also search for this author inPubMed Google Scholar
  11. Hoey Koh
    You can also search for this author inPubMed Google Scholar
  12. Lisa Simms
    You can also search for this author inPubMed Google Scholar
  13. Melissa Barker
    You can also search for this author inPubMed Google Scholar
  14. Barbara Leggett
    You can also search for this author inPubMed Google Scholar
  15. Joan Levine
    You can also search for this author inPubMed Google Scholar
  16. Myungjin Kim
    You can also search for this author inPubMed Google Scholar
  17. Amy J French
    You can also search for this author inPubMed Google Scholar
  18. Stephen N Thibodeau
    You can also search for this author inPubMed Google Scholar
  19. Jeremy Jass
    You can also search for this author inPubMed Google Scholar
  20. Robert Haile
    You can also search for this author inPubMed Google Scholar
  21. Peter W Laird
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toPeter W Laird.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Weisenberger, D., Siegmund, K., Campan, M. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Nat Genet 38, 787–793 (2006). https://doi.org/10.1038/ng1834

Download citation

This article is cited by

Associated content