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

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly... 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' 1,2 . However, the existence of CIMP has been challenged 3,4 . 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 BRAFmutation (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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Genetics Springer Journals

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References (26)

Publisher
Springer Journals
Copyright
Copyright © 2006 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Human Genetics; Cancer Research; Agriculture; Gene Function; Animal Genetics and Genomics
ISSN
1061-4036
eISSN
1546-1718
DOI
10.1038/ng1834
Publisher site
See Article on Publisher Site

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' 1,2 . However, the existence of CIMP has been challenged 3,4 . 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 BRAFmutation (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.

Journal

Nature GeneticsSpringer Journals

Published: Jun 25, 2006

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