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

Nature Genetics volume 38, pages 787793 (2006) | Download Citation

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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.

Author information

Author notes

    • Daniel J Weisenberger
    •  & Kimberly D Siegmund

    These authors contributed equally to this work.

Affiliations

  1. Departments of Surgery and of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176, 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, California 90089-9176, USA.

    • Kimberly D Siegmund
    • , Joan Levine
    •  & Robert Haile
  3. Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Herston, Queensland 4006, Australia.

    • Joanne Young
    • , Daniel Buchanan
    •  & Melissa Barker
  4. Department of Pathology, Seoul National University Hospital, Seoul 110-744, Korea.

    • Gyeong Hoon Kang
  5. Institute for Women's Health, Department of Gynaecological Oncology, University College London, London WC1E 6DH, UK.

    • Martin Widschwendter
  6. Conjoint Gastroenterology Laboratory, Royal Brisbane & Women's Hospital Research Foundation, Clinical Research Centre, Herston, Queensland 4006, Australia.

    • Hoey Koh
    • , Lisa Simms
    •  & Barbara Leggett
  7. Departments of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

    • Amy J French
    •  & Stephen N Thibodeau
  8. Department of Pathology, McGill University, Montreal QC H3A 2B4, Canada.

    • Jeremy Jass

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter W Laird.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Methylation-specific PCR of the New CIMP Panel on CIMP+ and CIMP− colon tumor DNA samples.

  2. 2.

    Supplementary Table 1

    MethyLight reaction details.

  3. 3.

    Supplementary Table 2

    New CIMP Classification Panel.

  4. 4.

    Supplementary Table 3

    Cross-panel classification error rates among various CIMP classification panels, expressed as percentages.

  5. 5.

    Supplementary Table 4

    Methylation frequency by KRAS and BRAF status.

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DOI

https://doi.org/10.1038/ng1834

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