CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.
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.
Weisenberger
Daniel J
DJ
Department of Surgery, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176, USA.
Siegmund
Kimberly D
KD
Campan
Mihaela
M
Young
Joanne
J
Long
Tiffany I
TI
Faasse
Mark A
MA
Kang
Gyeong Hoon
GH
Widschwendter
Martin
M
Weener
Deborah
D
Buchanan
Daniel
D
Koh
Hoey
H
Simms
Lisa
L
Barker
Melissa
M
Leggett
Barbara
B
Levine
Joan
J
Kim
Myungjin
M
French
Amy J
AJ
Thibodeau
Stephen N
SN
Jass
Jeremy
J
Haile
Robert
R
Laird
Peter W
PW
D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D042822:Genomic Instability; D006801:Humans; D018895:Microsatellite Repeats; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf