Increased methylation variation in epigenetic domains across cancer types

By Kasper D. Hansen, Winston Timp, Héctor Corrada Bravo, S. Sabunciyan, Benjamin Langmead, O. G. McDonald, Bo Wen, Hao Wu, Yun Liu, D. Diep and 4 more. Nature Genetics, 2011

1,095 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d60a50edfed57fbc51cf2062de78a035fd440582

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Citations in the corpus

Epigenetic Determinants of Cancer. (2016, background): “…recognized change in DNA methylation patterns in cancer cells was regional decreases in this modification (Feinberg and Vogelstein 1983; Ehrlich and Lacey 2013), now recognized by genome-wide analyses as a global DNA hypomethylation (Hansen et al. 2011; Berman et al. 2012; Bert et al. 2013).”
Analysing and interpreting DNA methylation data (2012, methodology): “The magnitude of this effect can be assessed using the M bias plot and can be mitigated by discarding those positions among the sequencing reads that exhibit globally biased DNA methylation levels 37 .”
Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules (2012, background): “…filter out the 59 ends of reads that have apparent bisulfite nonconversion, which is common in the Illumina protocol presumably due to reannealing of base pairs adjacent to the adapter sequences which are methylated and thus have 100% base complementarity (Hansen et al. 2011; Berman et al. 2012).”
CG methylated microarrays identify a novel methylated sequence bound by the CEBPB|ATF4 heterodimer that is active in vivo (2013, background): “Recent global analysis of gene expression and CG methylation has identified many examples of methyla- tion at active promoters (Eckhardt et al. 2006; Weber et al. 2007; Hansen et al. 2011).”