Serrated adenoma of the colorectum and the DNA-methylator phenotype

Abstract

Serrated adenomas (SA) of the colorectum show features intermediate between hyperplastic polyps (HP) and adenomas. HP and SA are related lesions and there is now strong evidence for a 'serrated-polyp pathway' to colorectal cancer (CRC) that is largely independent of the classic adenoma-to-carcinoma sequence. A recently recognized lesion in this pathway is a HP variant characterized by relatively large size, atypical histology and proximal location in the colorectum. This HP variant has been given a variety of names in the literature including 'sessile SA' and 'type I SA'. Because this lesion lacks the traditional cytology of colorectal adenoma and in order to avoid confusion with SA, it is referred to in this review as sessile serrated polyp. SA are characterized by a heterogeneous group of changes at the molecular level, but a high proportion have BRAF mutations and DNA methylation. They may develop in HP or sessile serrated polyps, or may arise de novo. In the serrated-polyp pathway, the advent of genetic instability is likely to be an important rate-limiting step that drives rapid neoplastic evolution. Methylation and inactivation of the DNA repair genes MLH1 and MGMT (O-6-methylguanine-DNA methyltransferase) have been proposed as critical steps leading to genetic instability. Stretches of DNA rich in the bases guanine and cytosine (CpG islands; where p represents a phosphodiester bond linking adjacent cytosine and guanine bases) that are normally unmethylated may become methylated in malignant human colorectal tumors. Subsets of colorectal cancers with an unusually high number of methylated CpG islands have been described as having the 'CpG-island-methylator phenotype'. It is possible that many, if not all, CRCs with the CpG-island-methylator phenotype evolve through the serrated-polyp pathway that would, therefore, explain approximately 20% of all CRCs. The current lack of guidelines for managing serrated polyps may explain the static incidence of proximal CRC, despite the falling incidence rates for left-sided CRC during the same time period.