Article abstract
Nature Genetics 41, 178 - 186 (2009)
Published online: 18 January 2009 | doi:10.1038/ng.298
The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores
Rafael A Irizarry1,2,8, Christine Ladd-Acosta2,3,8, Bo Wen2,3, Zhijin Wu4, Carolina Montano2,3, Patrick Onyango2,3, Hengmi Cui2,3, Kevin Gabo2,3, Michael Rongione2,3, Maree Webster5, Hong Ji2,3, James B Potash2,6, Sarven Sabunciyan2,7 & Andrew P Feinberg2,3,8
Abstract
For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45–65%) of the locations of colon cancer–related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
- Center for Epigenetics, Institute for Basic Biomedical Sciences, Baltimore, Maryland 21205, USA.
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
- Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
- Stanley Laboratory of Brain Research, Uniformed Services University of Health Sciences, Bethesda, Maryland 20892, USA.
- Departments of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
- Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
- These authors contributed equally to this work.
Correspondence to: Rafael A Irizarry1,2,8 e-mail: rafa@jhu.edu
Correspondence to: Andrew P Feinberg2,3,8 e-mail: afeinberg@jhu.edu
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