TY  - JOUR
A1  - Hinoue, Toshinori
A1  - Weisenberger, Daniel J.
A1  - Lange, Christopher P.E.
A1  - Shen, Hui
A1  - Byun, Hyang-Min
A1  - Van Den Berg, David
A1  - Malik, Simeen
A1  - Pan, Fei
A1  - Noushmehr, Houtan
A1  - van Dijk, Cornelis M.
A1  - Tollenaar, Rob A.E.M.
A1  - Laird, Peter W.
T1  - Genome-scale analysis of aberrant DNA methylation in colorectal cancer
Y1  - 2012/02/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 271 
EP  - 282 
DO  - 10.1101/gr.117523.110 
VL  - 22 
IS  - 2 
UR  - http://genome.cshlp.org/content/22/2/271.abstract 
N2  - 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 BRAFV600E 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. 
ER  -