title: Increased methylation variation in epigenetic domains across cancer types.
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.
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Kasper Daniel
authors.initials: KD
authors.lastname: Hansen
authors.forename: Winston
authors.initials: W
authors.lastname: Timp
authors.forename: Héctor Corrada
authors.initials: HC
authors.lastname: Bravo
authors.forename: Sarven
authors.initials: S
authors.lastname: Sabunciyan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Langmead
authors.forename: Oliver G
authors.initials: OG
authors.lastname: McDonald
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Dinh
authors.initials: D
authors.lastname: Diep
authors.forename: Eirikur
authors.initials: E
authors.lastname: Briem
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Irizarry
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D057890:Epigenomics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000145:classification* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D013447:Sulfites
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D013447:Sulfites; C042345:hydrogen sulfite