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.