title: Genome-scale analysis of aberrant DNA methylation in colorectal cancer.
abstract: Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. Here we performed comprehensive genome-scale DNA methylation profiling of 125 colorectal tumors and 29 adjacent normal tissues. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. A CIMP-high (CIMP-H) subgroup, which exhibits an exceptionally high frequency of cancer-specific DNA hypermethylation, is strongly associated with MLH1 DNA hypermethylation and the BRAF(V600E) mutation. A CIMP-low (CIMP-L) subgroup is enriched for KRAS mutations and characterized by DNA hypermethylation of a subset of CIMP-H-associated markers rather than a unique group of CpG islands. Non-CIMP tumors are separated into two distinct clusters. One non-CIMP subgroup is distinguished by a significantly higher frequency of TP53 mutations and frequent occurrence in the distal colon, while the tumors that belong to the fourth group exhibit a low frequency of both cancer-specific DNA hypermethylation and gene mutations and are significantly enriched for rectal tumors. Furthermore, we identified 112 genes that were down-regulated more than twofold in CIMP-H tumors together with promoter DNA hypermethylation. These represent ∼7% of genes that acquired promoter DNA methylation in CIMP-H tumors. Intriguingly, 48/112 genes were also transcriptionally down-regulated in non-CIMP subgroups, but this was not attributable to promoter DNA hypermethylation. Together, we identified four distinct DNA methylation subgroups of CRC and provided novel insight regarding the role of CIMP-specific DNA hypermethylation in gene silencing.
authors.affiliation: Department of Surgery and Department of Biochemistry and Molecular Biology, University of Southern California, USC Epigenome Center, Los Angeles, California 90089-9601, USA.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hinoue
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Christopher P E
authors.initials: CP
authors.lastname: Lange
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Hyang-Min
authors.initials: HM
authors.lastname: Byun
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Simeen
authors.initials: S
authors.lastname: Malik
authors.forename: Fei
authors.initials: F
authors.lastname: Pan
authors.forename: Houtan
authors.initials: H
authors.lastname: Noushmehr
authors.forename: Cornelis M
authors.initials: CM
authors.lastname: van Dijk
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins