CpG island methylator phenotype in colorectal cancer

Aberrant methylation of promoter region CPG islands is associated with tran scriptional inactivation of tumor-suppressor genes in neoplasia, To underst and global patterns of CpG island methylation in colorectal cancer, we have used a recently developed technique called methylated CpG island amplifica tion to examine 30 newly cloned differentially methylated DNA sequences. Of these 30 clones, 19 (63%) were progressively methylated in an age-dependen t manner in normal colon, 7 (23%) were methylated in a cancer-specific mann er, and 3 (13%) were methylated only in cell lines, Thus, a majority of CpG islands methylated in colon cancer are also methylated in a subset of norm al colonic cells during the process of aging, In contrast, methylation of t he cancer-specific clones was Pound exclusively in a subset of colorectal c ancers, which appear to display a CpG island methylator phenotype (CIMP), C IMP+ tumors also have a high incidence of p16 and THBS1 methylation, and th ey include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation, We thus define a pathway in color ectal cancer that appears to be responsible for the majority of sporadic tu mors with mismatch repair deficiency.