Increased methylation variation in epigenetic domains across cancer types

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. We therefore hypothesized that these colon cDMRs might also be cDMRs for other cancer types. For colon, lung, breast, thyroid, and Wilms tumors, we show stochastic variation in methylation within each tumor type, but involving the same loci across tumor types, with intermediate values of variation for premalignant adenomas. Furthermore, whole genome bisulfite sequencing of colon cancer shows relative hypomethylation of large (5 kb – 10 Mb) blocks encompassing half the genome and one-third of annotated genes, and is associated with extreme heterogeneity of gene expression, as well as loss of sharply delimited methylation boundaries at CpG islands. 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.