Increased methylation variation in epigenetic domains across cancer types.
|Title||Increased methylation variation in epigenetic domains across cancer types.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Hansen K D, Timp W, Bravo H C, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E, Zhang K, Irizarry RA, Feinberg AP|
|Date Published||2011 Aug|
|Keywords||CpG Islands, DNA Methylation, DNA, Neoplasm, Epigenomics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Variation, Humans, Neoplasms, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic, Sulfites, Tumor Markers, Biological|
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 tissue, 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. We suggest a model for cancer involving loss of epigenetic stability of well-defined genomic domains that underlies increased methylation variability in cancer that may contribute to tumor heterogeneity.
|Alternate Journal||Nat. Genet.|