DNA methylation of shelf, shore and open sea CpG positions distinguish high microsatellite instability from low or stable microsatellite status colon cancer stem cells

To investigate the genome-wide methylation of genetically characterized colorectal cancer stem cell (CR-CSC) lines. Eight CR-CSC lines were isolated from primary colorectal cancer (CRC) tissues, cultured and characterized for aneuploidy, mutational status of CRC-related genes and microsatellite instability (MSI). Genome-wide DNA methylation was assessed by MethylationEPIC microarray. We describe a distinctive methylation pattern that is maintained following passages in immune-compromised mice. We identified an epigenetic CR-CSC signature associated with MSI. We noticed that the preponderance of the differentially methylated positions do not reside at CpG islands, but spread to shelf and open sea regions. Given that CRCs with MSI-high status have a lower metastatic potential, the identification of a MSI-related methylation signature could provide new insights and possible targets into metastatic CRC.