Figure 2: Epigenetic alterations may differentiate the traditional and serrated pathway at early stage of tumor development. (a) The serrated and traditional pathways show clinical differences, especially when referred to the site of origin of the tumor. The serrated pathway tends to be localized to the proximal (right) colon; the traditional to the distal (left) colon. The main molecular alterations that clearly distinguish the two pathways are the presence (+)/absence (−) of the CIMP phenotype and different genetic characteristics (BRAF/MSI versus APC/CIN). (b) The colonic epithelium consists of spatially separated, nonproliferative/differentiated cells at the tip of the villi, marked by cytokeratin 20 and proliferative/undifferentiated cell populations marked by Ki67. The molecular mechanisms underlying CIMP and CIN are still unknown; however, these alterations may evolve in a nonrandom fashion. According to the top-down model [31], the traditional pathway may arise from genetic lesions (APC mutations) confined to the upper crypt compartment. In contrast, the serrated pathway may originate in the lower crypt compartment by yet uncharacterized genetic and/or epigenetic lesions. Current evidences support the idea that the specific functions played in the lower compartment are maintained by an epigenetic program finely regulated by PRCs [13, 3235]. Initial lesions in cells of this compartment may predispose to the epigenetic characteristics of the adult cancer through an “epigenetic memory.” This may explain why these specific precursor lesions proliferate downward or laterally, are age-related, rapidly progressive, and prone to CIMP. APC, adenomatous polyposis coli; MSI, microsatellite instability; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; polycomb repressive complexes (PRCs).