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Background & Aims: Methylation of CpG islands is increasingly recognized as an important event in colorectal carcinogenesis. We evaluated the extent of CpG island methylation in 426 sporadic colorectal cancers to define its relationship to microsatellite instability and to describe its clinicopathologic and genetic features. METHODS: Fresh cancer tissue was obtained from 417 consecutive individuals undergoing curative surgery for sporadic colorectal cancer. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at MINT 1, 2, 12, and 31 loci was assessed by bisulfite PCR. Microsatellite instability and K-ras and p53 status were determined using microsatellite PCR, restriction enzyme-mediated PCR, and immunohistochemistry, respectively. RESULTS: Individual loci were commonly methylated, but locus-specific phenotypic changes were not seen. CpG island methylation was associated with right-sided location, female sex, and older age, as well as high tumor grade, mucinous type, wild-type P53, microsatellite instability, and K-ras mutations. More than half of tumors showing CpG island methylation were microsatellite stable. Compared with microsatellite unstable cancers, they were more commonly left-sided, had fewer intraepithelial lymphocytes, presented later, and had a worse outcome. CONCLUSIONS: Colorectal cancers with CpG island methylation have distinct clinicopathologic features and in some cases lead to sporadic microsatellite unstable cancers.