Increased methylation variation in epigenetic domains across cancer types

Kasper Daniel Hansen, Winston Timp, Héctor Corrada Bravo, Sarven Sabunciyan, Benjamin Langmead, Oliver G. McDonald, Bo Wen, Hao Wu, Yun Liu, Dinh Diep, Eirikur Briem, Kun Zhang, Rafael A. Irizarry, Andrew P. Feinberg

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)768-775
Number of pages8
JournalNature genetics
Volume43
Issue number8
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Hansen, K. D., Timp, W., Bravo, H. C., Sabunciyan, S., Langmead, B., McDonald, O. G., Wen, B., Wu, H., Liu, Y., Diep, D., Briem, E., Zhang, K., Irizarry, R. A., & Feinberg, A. P. (2011). Increased methylation variation in epigenetic domains across cancer types. Nature genetics, 43(8), 768-775. https://doi.org/10.1038/ng.865