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

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Authors
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, S; Barker, M; Leggett, B; Levine, J; Kim, M J; French, A J; Thibodeau, S N; Jass, F; Haile, R; Laird, P W
Issue Date
2006-06-25
Publisher
Nature Publishing Group
Citation
Nat. Genet. 38(7), 787-793 (2006).
Keywords
Colorectal Neoplasms/*genetics*CpG Islands*DNA MethylationDNA Repair/geneticsDNA, Neoplasm/chemistry/geneticsEpigenesis, GeneticGene SilencingGenomic InstabilityHumansMicrosatellite RepeatsModels, Genetic*MutationPhenotypePromoter Regions, GeneticProto-Oncogene Proteins B-raf/*genetics
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.
ISSN
1061-4036
Language
English
URI
http://hdl.handle.net/10371/10052
DOI
https://doi.org/10.1038/ng1834
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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