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

Daniel J. Weisenberger, Kimberly D. Siegmund, Mihaela Campan, Joanne Young, Tiffany I. Long, Mark A. Faasse, Gyeong Hoon Kang, Martin Widschwendter, Deborah Weener, Daniel Buchanan, Hoey Koh, Lisa Simms, Melissa Barker, Barbara Leggett, Joan Levine, Myungjin Kim, Amy J. French, Stephen N. Thibodeau, Jeremy Jass, Robert HailePeter W. Laird

Research output: Contribution to journalArticle

1352 Scopus citations

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'. However, the existence of CIMP has been challenged. 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 BRAF mutation (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.

Original languageEnglish (US)
Pages (from-to)787-793
Number of pages7
JournalNature Genetics
Volume38
Issue number7
DOIs
StatePublished - Jul 1 2006

ASJC Scopus subject areas

  • Genetics

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    Weisenberger, D. J., Siegmund, K. D., Campan, M., Young, J., Long, T. I., Faasse, M. A., Kang, G. H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., Barker, M., Leggett, B., Levine, J., Kim, M., French, A. J., Thibodeau, S. N., Jass, J., ... Laird, P. W. (2006). CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nature Genetics, 38(7), 787-793. https://doi.org/10.1038/ng1834