Molecular Features of the Serrated Pathway to Colorectal Cancer: Current Knowledge and Future Directions

Abstract

Serrated lesions are the precursor lesions of a new model of colorectal carcinogenesis. From a molecular standpoint, the serrated pathway is thought to be responsible for up to 30% of all colorectal cancer cases. The three major processes of this molecular mechanism are alterations in the mitogen-activated protein kinase pathway, production of the CpG island methylation phenotype, and generation of microsatellite instability. Other contributing processes are activation of WNT, alterations in the regulation of tumor suppressor genes, and alterations in microRNAs or in MUC5AC hypomethylation. Although alterations in the serrated pathway also contribute, their precise roles remain obscure because of the various methodologies and definitions used by different research groups. This knowledge gap affects clinical assessment of precursor lesions for their carcinogenic risk. The present review describes the current literature reporting the molecular mechanisms underlying each type of serrated lesion and each phenotype of serrated pathway colorectal cancer, identifying those areas that merit additional research. We also propose a unified serrated carcinogenesis pathway combining molecular alterations and types of serrated lesions, which ends in different serrated pathway colorectal cancer phenotypes depending on the route followed. Finally, we describe some key issues that need to be addressed in order to incorporate the newest technologies in serrated pathway research and to improve overall knowledge for developing specific prevention strategies and new therapeutic targets.

Keywords: BRAF; Carcinogenesis; Colorectal; Molecular biology; Polyps.

Fig. 1

(A) White light high-resolution endoscopic image of a sessile serrated lesion (SSL): dark spots inside the crypts, an irregular shape, indistinct borders and a cloud-like surface. (B) SSL showing typical serration (H&E, ×10). Crypts show pronounced basal dilation and horizontal spreading in an “L” shape.

Fig. 2

Endoscopic appearance of a sessile serrated lesion with cytological dysplasia. The nodular element (containing dysplasia) is more apparent than the rest of the lesion, increasing the likelihood of incomplete resection of the whole lesion.

Fig. 3

Schematic view of serrated pathway progression. mRNA, microRNA; HP, hyperplastic polyp; CIMP, CpG island hypermethylator phenotype; MMR, mismatch repair system; SSL, sessile serrated lesion; SSL-CD, SSL with cytological dysplasia; CIMP-H, CIMP-high; MSI, microsatellite instability; MSS, microsatellite stability; TSA, traditional serrated adenoma; CIMP-L, CIMP-low.