Frequent CpG Island Methylation in Serrated Adenomas of the Colorectum

Abstract

Serrated adenomas are characterized by a saw-toothed growth pattern with epithelial dysplasia (intraepithelial neoplasia). The CpG island methylator phenotype (CIMP) is a recently described mechanism for tumorigenesis in colorectal carcinomas and adenomas characterized by methylation of multiple CpG islands. The role of these epigenetic alterations in the pathogenesis of serrated adenomas is not clear. We therefore evaluated CIMP in 22 sporadic serrated adenomas and 6 serrated adenomas with multiple (6 to 10) hyperplastic polyps, including 5 with admixed hyperplastic glands and adenomatous glands, and compared the results with 34 conventional adenomas. Bisulfite methylation-specific polymerase chain reaction was used for the p16 and hMLH1 genes, and three MINT (methylated in tumor) loci (MINT1, MINT2, and MINT31). Patients with sporadic serrated adenomas had a higher frequency of hyperplastic polyps (1.3 +/- 1.6) as compared to patients with tubular adenomas (0.4 +/- 0.9, P = 0.02). Mean number of methylated sites was significantly higher in sporadic serrated adenomas (2.0 +/- 1.7) than in tubular adenomas (0.8 +/- 0.9, P = 0.00001). Sporadic serrated adenomas had significantly more frequent methylation of MINT1 (48%, 10 of 22) and MINT2 (71%, 15 of 21) than tubular adenomas (9%, 3 of 34, P = 0.001; and 18%, 6 of 34, P = 0.0001), respectively. Concordant methylation of two or more sites (CIMP-high) was also more frequent in sporadic serrated adenomas (68%, 15 of 22) than in tubular adenomas (18%, 6 of 34, P = 0.0005). All five serrated adenomas with admixed hyperplastic glands and adenomatous glands were CIMP-high. Our results indicate that CpG island methylation is common in sporadic serrated adenomas and may play an important role in their pathogenesis.