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

Cited 1291 time in Web of Science Cited 1357 time in Scopus
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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