Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores

Alterations in DNA methylation (DNAm) in cancer have been known for 25 years, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes1. 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 islands2,3. 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 surprising overlap (45-65%) of the location 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 non-colon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, and they are consistent with the epigenetic progenitor model of cancer4, that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.