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

Cited 1434 time in Web of Science Cited 1525 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/*geneticsDNA Repair/geneticsDNA, Neoplasm/chemistry/geneticsEpigenesis, GeneticGene SilencingGenomic InstabilityHumansMicrosatellite RepeatsModels, GeneticPhenotypePromoter Regions, GeneticProto-Oncogene Proteins B-raf/*geneticsCpG IslandsDNA MethylationMutation
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
https://hdl.handle.net/10371/10052
DOI
https://doi.org/10.1038/ng1834
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