Figure 2.

Molecular dependencies of adenoma–carcinoma and serrated pathways. In the classical adenoma–carcinoma pathway, activation of both the Wnt pathway via APC loss and MEK–ERK pathway via the KRAS oncogene followed by tumor suppressor inactivation of SMAD4 and TP53 develops microsatellite stable (MSS), CpG-island methylator phenotype (CIMP)-low/negative cancers with chromosomal instability (CIN). In the serrated pathway, activation of the MEK–ERK pathway occurs via the KRAS or BRAF oncogenes in parallel with CIMP-high related DNA methylation accumulation. This involves methylation of important genes such as CDKN2A/p16, MLH1, and CDX2. Methylation at the MLH1 promoter results in high microsatellite instability (MSI-H) cancers, while cases lacking MLH1 methylation result in low microsatellite instability (MSI-L) cancers. Other DNA repair genes, such as MGMT, also get affected by promoter methylation. Mutations in various genes most likely occur later during progression of the serrated lesions, leading to dysregulation of the major cancer pathways, including due to inactivation of the RNF43–ZNRF3 axis for Wnt pathway activation. Consensus molecular subtypes (CMS) expression phenotypes may be an early event occurring at the early lesion stage and may have important roles in the path to tumor development. Figure generated using BioRender.