Serrated colorectal polyps and the serrated neoplastic pathway: Emerging concepts in colorectal carcinogenesis

Abstract

Several investigators have recently proposed the concept of a ‘serrated neoplastic pathway’ to account for the development of a subset of colonic carcinomas that lack chromosomal instability and loss of heterozygosity. This pathway putatively involves several pathogenetically related polyps, including some hyperplastic polyps, the recently described sessile serrated polyp, serrated adenoma and mixed polyp; and is characterised by early BRAF mutations, DNA hypermethylation and microsatellite instability. Most hyperplastic polyps and sessile serrated polyps harbour mutations in BRAF, one gene involved in the mitogen-activated protein kinase pathway, and abnormal DNA methylation. Presumably, these genetic changes are sufficient to potentiate widespread genomic hypermethylation that ultimately affects the promoter regions of key DNA repair genes, such as hMLH-1 and O⁶-methylguanine methyltransferase, thereby silencing them from transcription and leading to progressive microsatellite instability. The morphological evolution of non-dysplastic serrated lesions (hyperplastic and sessile serrated polyps) to serrated adenomas, mixed polyps and/or colorectal carcinoma is believed to reflect the accumulation of these genetic events. The purpose of this review is to describe the morphological and molecular features of colorectal serrated polyps and to present the available data supporting the concept of a serrated neoplastic pathway of colorectal carcinogenesis.