Identification of the Methylator (Serrated) Colorectal Cancer Phenotype Through Precursor Serrated Polyps

PURPOSE: Colorectal cancers arise via cumulative genetic and molecular changes that cause mucosal instability, premalignant polyps, and malignant transformation. Distinct neoplastic pathways characterized by chromosomal instability, genetic mutation, and epigenetic methylation have been described, but their associated precursor polyps have not. This study analyzes characteristics of precursor polyps occurring within different molecular subtypes of sporadic colorectal cancer. METHODS: Colorectal cancers from a prospectively maintained frozen tissue bank were analyzed for microsatellite stability and promoter methylation, defined by the CpG island methylator phenotype. Patients with tumors meeting the following criteria were included: microsatellite stable and methylator-negative; microsatellite stable and methylator-positive; and microsatellite unstable and methylator-positive. Hereditary cancers were excluded. Patient demographics, colonoscopic and histologic polyp characteristics, operative reports, and pathology reports were reviewed. RESULTS: One hundred seven patients were included: 65, 20, and 22 patients in each group, respectively. The proportion of patients with synchronous polyps and polyp number, size, and location were similar. However, associated polyp histology varied according to tumor classification. Microsatellite stable tumors, regardless of methylator status, had a greater proportion of adenomas than microsatellite unstable tumors, which had an increased proportion of serrated polyps (P = 0.029). CONCLUSIONS: Patients with microsatellite unstable colorectal cancers demonstrate an increased serrated polyp-to-adenoma ratio compared with microsatellite stable cancers regardless of methylator status. Loss of microsatellite stability appears to be a key event in serrated polyp and cancer formation. An increased proportion of serrated polyps to adenomas discovered in patients on colonoscopy should arouse suspicion that cancers arising in these patients are probably microsatellite unstable.