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- Title
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.
- Authors
Weisenberger, Daniel J; Siegmund, Kimberly D; Campan, Mihaela; Young, Joanne; Long, Tiffany I; Faasse, Mark A; Kang, Gyeong Hoon; Widschwendter, Martin; Weener, Deborah; Buchanan, Daniel; Koh, Hoey; Simms, Lisa; Barker, Melissa; Leggett, Barbara; Levine, Joan; Kim, Myungjin; French, Amy J; Thibodeau, Stephen N; Jass, Jeremy; Haile, Robert; Laird, Peter W
- 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.
- Publication
Nature genetics, 2006, Vol 38, Issue 7, p787
- ISSN
1061-4036
- Publication type
Journal Article
- DOI
10.1038/ng1834