The causes and global patterns of aberrant methylation, in spite of its frequent occurrence in human cancers, remain poorly defined. In 1999, Toyota and colleagues reported that methylation of CpG islands of normal colonic mucosa was gradually lost as age advanced, and that aberrant methylation was linked to microsatellite instability. To understand these patterns better, these investigators examined the methylation status of CpG islands in 30 differentially methylated loci (including genes known to occur in colorectal cancers such as p16 and THBS1) derived from a panel of 50 primary colorectal cancers and 15 adeno-mas.119 Characterization of 26 clones in this study revealed that the majority of CpG island methylation events in 19/26 (73%) clones of colorectal cancers were frequently methylated (averaging 75%, range 30-100%) and related to incremental hypermethylation in normal colon as an age-related phenomenon. Most other methylation events, 7/26 (27%), occurred in a distinct subset of clones from colorectal cancers and adenomas with a significantly lower frequency of methylation (range 10-50%) that appeared to have a new phenotype, designated the CpG island methylation phenotype (CIMP). Age-related hypermethylation was very frequent, affected a large number of cells, occurred in all persons, not just in cancer patients, was gene and tissue specific, and was believed to result from physiological processes. In contrast, cancer-specific hypermethylation was relatively infrequent, and was not found in normal colon mucosa. Next, in a study of 50 colorectal tumors and adenomas, the panel could be divided into two groups according to their hypermethylator status. One group displayed a high level of cancer-specific methylation in which all tumors had methylation of three or more loci (averaging 5.1 loci/tumor), including a high incidence of p16 and THBS1, and the other group in which methylation was extremely rare (an average of 0.3 loci/tumor). In sharp contrast, the frequency of age-related hypermethylation was not significantly different between the two groups of tumors. The CIMP+ tumors included the majority of sporadic colorectal cancers with microsatellite instability related to methylation of the mismatch repair gene hMLH1. The data suggested the existence of a pathway in colorectal cancer that was responsible for the risk of mismatch repair-positive sporadic tumors.119
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