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Genome Med. 2014 Aug 26;6(8):61. doi: 10.1186/s13073-014-0061-y. eCollection 2014.

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

Author information

1
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD USA ; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA.
2
Center for Bioinformatics and Computational Biology, Department of Computer Science, University of Maryland, College Park, MD USA.
3
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD USA ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA.
4
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA.
5
Departments of Surgery and Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Baltimore, MD USA.
6
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD USA ; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD USA ; Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Baltimore, MD USA.
7
Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD USA ; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA ; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute and Department of Biostatistics, Harvard School of Public Health, Boston, MA USA.

Abstract

BACKGROUND:

One 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).

METHODS:

Here 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.

RESULTS:

We 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.

CONCLUSION:

Thus hypomethylated blocks appear to be a universal defining epigenetic alteration in human cancer, at least for common solid tumors.

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