title: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.
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.
authors.affiliation: Department of Surgery, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90089-9176, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Mihaela
authors.initials: M
authors.lastname: Campan
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Tiffany I
authors.initials: TI
authors.lastname: Long
authors.forename: Mark A
authors.initials: MA
authors.lastname: Faasse
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Deborah
authors.initials: D
authors.lastname: Weener
authors.forename: Daniel
authors.initials: D
authors.lastname: Buchanan
authors.forename: Hoey
authors.initials: H
authors.lastname: Koh
authors.forename: Lisa
authors.initials: L
authors.lastname: Simms
authors.forename: Melissa
authors.initials: M
authors.lastname: Barker
authors.forename: Barbara
authors.initials: B
authors.lastname: Leggett
authors.forename: Joan
authors.initials: J
authors.lastname: Levine
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jass
authors.forename: Robert
authors.initials: R
authors.lastname: Haile
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
mesh_terms: 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*
chemical_list: D004273:DNA, Neoplasm; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf