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.

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Acknowledgements

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

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

Correspondence toPeter W Laird.

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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

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