Unique DNA Methylation Profiles in CpG Island Methylator Phenotype Colon Cancers

DNA methylation is essential for normal development and is frequently altered in cancers. A subset of colorectal cancers was postulated to have the CpG Island Methylator Phenotype (CIMP), a higher propensity for CpG island DNA methylation. The validity of CIMP, its molecular basis, and its prognostic values are highly controversial. Utilizing MBD-isolated Genome Sequencing, we mapped and compared genome-wide DNA methylation profiles of normal, non-CIMP, and CIMP colon specimens. We discovered 5,001 sites that were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal colon. Additional 1,728 sites were hypermethylated in CIMP tumors only. 88% of these were located in CpG islands, unequivocally demonstrating on a genome-wide level that these tumors were appropriately named. 39% are adjacent to sites hypermethylated in all tumors and represent more extensive hypermethylation in these areas, a novel feature of CIMP. These observations suggest defects in controlling DNA methylation seeding and spreading in CIMP and serve as an important first step in delineating such molecular mechanisms, which can form the basis of novel cancer therapies.