CpG island methylation in colorectal adenomas

Methylation of cytosines in CpG islands silences gene expression. CpG islan d methylator phenotype (CIMP) in colorectal cancers is characterized by abn ormal methylation of multiple CpG islands including those in several tumor suppressor genes such as p16, hMLH1, and THBS1. CpG island methylation has not been well characterized in adenomas. We evaluated methylation status at p16, MINT2, and MINT31 loci, which are frequently methylated in colorectal carcinomas, in 108 colorectal adenomas from a prospective study of 50 pati ents without cancer. Methylation at one or more loci was present in 48% (52 of 108) of adenomas with 25% (19 of 76) CIMP-high (two or more methylated loci) and 32% (24 of 76) CIMP-low (one methylated locus). The p16 gene was methylated in 27% (19 of 71) of adenomas. Methylation status of different a denomas from the same patient was not correlated (odds ratio, 0.93; P = 0.7 7). Adenomas with tubulovillous or villous, histology were frequently methy lated: 73% (17 of 26) versus 41% (35 of 85) of tubular adenomas (odds ratio , 3.46; P = 0.02). High levels of microsatellite instability were more freq uent in adenomas without methylation (13% versus 2%; odds ratio, 8.48; P = 0.05). Our results indicate that methylation plays an important role early in colorectal tumorigenesis. CpG island methylation is more common in adeno mas with tubulovillous/villous histology, a characteristic associated with more frequent predisposition to invasive carcinoma. Methylation is distinct from microsatellite instability and develops in individual adenomas rather than resulting from a field defect in an Individual patient.