Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors

BackgroundOne of the most provocative recent observations in cancer epigenetics is the discovery of large hypomethylated blocks, including single copy genes, in colorectal cancer, that correspond in location to heterochromatic LOCKs (large organized chromatin lysine-modifications) and LADs (lamin-associated domains).MethodsHere we performed a comprehensive genome-scale analysis of 10 breast, 28 colon, nine lung, 38 thyroid, 18 pancreas cancers, and five pancreas neuroendocrine tumors as well as matched normal tissue from most of these cases, as well as 51 premalignant lesions. We used a new statistical approach that allows the identification of large hypomethylated blocks on the Illumina HumanMethylation450 BeadChip platform.ResultsWe find that hypomethylated blocks are a universal feature of common solid human cancer, and that they occur at the earliest stage of premalignant tumors and progress through clinical stages of thyroid and colon cancer development. We also find that the disrupted CpG islands widely reported previously, including hypermethylated island bodies and hypomethylated shores, are enriched in hypomethylated blocks, with flattening of the methylation signal within and flanking the islands. Finally, we found that genes showing higher between individual gene expression variability are enriched within these hypomethylated blocks.ConclusionThus hypomethylated blocks appear to be a universal defining epigenetic alteration in human cancer, at least for common solid tumors.

[1]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[2]  S. Hannenhalli,et al.  Determinants of expression variability , 2014, Nucleic acids research.

[3]  I. Korf,et al.  Large-scale methylation domains mark a functional subset of neuronally expressed genes. , 2011, Genome research.

[4]  Peter W. Laird,et al.  Interplay between the Cancer Genome and Epigenome , 2013, Cell.

[5]  Israel Steinfeld,et al.  Molecular and Cellular Pathobiology Molecular Rules Governing De Novo Methylation in Cancer , 2022 .

[6]  Rafael A Irizarry,et al.  Frozen robust multiarray analysis (fRMA). , 2010, Biostatistics.

[7]  David T. W. Jones,et al.  Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing , 2014, Nature.

[8]  A. Feinberg,et al.  Large-scale hypomethylated blocks associated with Epstein-Barr virus–induced B-cell immortalization , 2014, Genome research.

[9]  P. Laird,et al.  Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina–associated domains , 2011, Nature Genetics.

[10]  Jeffrey T Leek,et al.  Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. , 2012, International journal of epidemiology.

[11]  Vasyl Pihur,et al.  Gene expression anti-profiles as a basis for accurate universal cancer signatures , 2012, BMC Bioinformatics.

[12]  Mark D. Robinson,et al.  Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity , 2010, Nature Cell Biology.

[13]  E. Cibas,et al.  The Bethesda System for Reporting Thyroid Cytopathology , 2009, Springer International Publishing.

[14]  A. Feinberg,et al.  Hypomethylation distinguishes genes of some human cancers from their normal counterparts , 1983, Nature.

[15]  Nianxiang Zhang,et al.  Age-related epigenetic drift in the pathogenesis of MDS and AML , 2014, Genome research.

[16]  A. Feinberg,et al.  Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells , 2009, Nature Genetics.

[17]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..

[18]  Kristian Helin,et al.  Histone lysine demethylases as targets for anticancer therapy , 2013, Nature Reviews Drug Discovery.

[19]  Brian J. Stevenson,et al.  Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. , 2012, Genome research.

[20]  R. Irizarry,et al.  A gene expression bar code for microarray data , 2007, Nature Methods.

[21]  H. Kitchener,et al.  Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation , 2012, Genome Medicine.

[22]  B. Horsthemke,et al.  Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma , 1989, Human Genetics.

[23]  Matthew N. McCall,et al.  The Gene Expression Barcode: leveraging public data repositories to begin cataloging the human and murine transcriptomes , 2010, Nucleic Acids Res..

[24]  Héctor Corrada Bravo,et al.  Epiviz: interactive visual analytics for functional genomics data , 2014, Nature Methods.

[25]  A. Feinberg,et al.  Increased methylation variation in epigenetic domains across cancer types , 2011, Nature Genetics.

[26]  L. Wessels,et al.  Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions , 2008, Nature.