Increased methylation variation in epigenetic domains across cancer types
Menée sur 290 échantillons de tissus tumoraux et de tissus sains prélevés sur des patients atteints d'un néphroblastome ou d'un cancer du côlon, du sein, du poumon ou de la thyroïde, cette étude met en évidence une variabilité accrue de la méthylation de domaines génomiques particuliers
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.
Nature Genetics 2011