TY - JOUR
T1 - CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer
AU - Weisenberger, Daniel J.
AU - Siegmund, Kimberly D.
AU - Campan, Mihaela
AU - Young, Joanne
AU - Long, Tiffany I.
AU - Faasse, Mark A.
AU - Kang, Gyeong Hoon
AU - Widschwendter, Martin
AU - Weener, Deborah
AU - Buchanan, Daniel
AU - Koh, Hoey
AU - Simms, Lisa
AU - Barker, Melissa
AU - Leggett, Barbara
AU - Levine, Joan
AU - Kim, Myungjin
AU - French, Amy J.
AU - Thibodeau, Stephen N.
AU - Jass, Jeremy
AU - Haile, Robert
AU - Laird, Peter W.
N1 - Funding Information:
The work described in this manuscript was supported by US National Institutes of Health grant R01 CA075090 awarded to P.W.L.
PY - 2006/7
Y1 - 2006/7
N2 - 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.
AB - 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.
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U2 - 10.1038/ng1834
DO - 10.1038/ng1834
M3 - Article
C2 - 16804544
AN - SCOPUS:33745541234
SN - 1061-4036
VL - 38
SP - 787
EP - 793
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -