Kasper Daniel Hansen 1 , 2 , Winston Timp 2 , 3 , 4 , Héctor Corrada Bravo 2 , 5 , Sarven Sabunciyan 2 , 6 , Benjamin Langmead 1 , 2 , Oliver G. McDonald 2 , 7 , Bo Wen 2 , 3 , Hao Wu 8 , Yun Liu 2 , 3 , Dinh Diep 9 , Eirikur Briem 2 , 3 , Kun Zhang 9 , Rafael A. Irizarry 1 , 2 , Andrew P. Feinberg 2 , 3
26 June 2011
Tumor heterogeneity is a major barrier to effective cancer diagnosis and treatment. We recently identified cancer-specific differentially DNA-methylated regions (cDMRs) in colon cancer, which also distinguish normal tissue types from each other, suggesting that these cDMRs might be generalized across cancer types. Here we show stochastic methylation variation of the same cDMRs, distinguishing cancer from normal, in colon, lung, breast, thyroid, and Wilms tumors, with intermediate variation in adenomas. Whole genome bisulfite sequencing shows these variable cDMRs are related to loss of sharply delimited methylation boundaries at CpG islands. Furthermore, we find hypomethylation of discrete blocks encompassing half the genome, with extreme gene expression variability. Genes associated with the cDMRs and large blocks are involved in mitosis and matrix remodeling, respectively. These data suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer and could contribute to tumor heterogeneity.