@article{Hinoue09062011,
author = {Hinoue, Toshinori and Weisenberger, Daniel J. and Lange, Christopher P.E. and Shen, Hui and Byun, Hyang-Min and Van Den Berg, David and Malik, Simeen and Pan, Fei and Noushmehr, Houtan and van Dijk, Cornelis M. and Tollenaar, Rob A.E.M. and Laird, Peter W.}, 
title = {Genome-scale analysis of aberrant DNA methylation in colorectal cancer},
year = {2011}, 
doi = {10.1101/gr.117523.110}, 
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 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.}, 
URL = {http://genome.cshlp.org/content/early/2011/06/09/gr.117523.110.abstract}, 
eprint = {http://genome.cshlp.org/content/early/2011/06/09/gr.117523.110.full.pdf+html}, 
journal = {Genome Research} 
}