RT Journal
A1 Easwaran, Hariharan
A1 Johnstone, Sarah
A1 VanNeste, Leander
A1 Ohm, Joyce
A1 Mosbruger, Tim
A1 Wang, Qiuju
A1 Aryee, Martin J
A1 Joyce, Patrick
A1 Ahuja, Nita
A1 Weisenberger, Dan
A1 Collisson, Eric
A1 Zhu, Jing-chun
A1 Yegnasubramanian, Srinivasan
A1 Matsui, William
A1 Baylin, Stephen B
T1 A DNA hypermethylation module for the stem/progenitor cell signature of cancer
JF Genome Research 
JO Genome Research 
YR 2012 
FD March 05 
DO 10.1101/gr.131169.111 
SP gr.131169.111 
UL http://genome.cshlp.org/content/early/2012/03/05/gr.131169.111.abstract 
AB Many DNA-hypermethylated cancer genes are occupied by the polycomb  (PcG) repressor complex in embryonic stem cells (ESC).  Their prevalence in the full spectrum of cancers, the exact context of chromatin involved, and their status in adult cell renewal systems are unknown. Using a genome-wide analysis, we demonstrate that approximately 75% of hypermethylated genes are marked by PcG in the context of bivalent chromatin in both ESC and adult stem/progenitor cells. A large number of these genes are key developmental regulators and a subset, which we call the "DNA hypermethylation module", comprise a portion of the PcG target genes that are downregulated in cancer. Genes with bivalent chromatin have a low, poised gene transcription state that has been shown to maintain stemness and self-renewal in normal stem cells. However, when DNA-hypermethylated in tumors, we find these genes are further repressed. We also show that the methylation status of these genes can cluster important subtypes of colon and breast cancers. By evaluating the subsets of genes that are methylated in different cancers with consideration of their chromatin status in ESCs, we provide evidence that DNA-hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer.  Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions.