Pathways of Colorectal Carcinogenesis

Abstract

Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.

Keywords: CRC; DNA mismatch repair; genomic instability; serrated polyp.

Figure 1.. Pathways of Colorectal Carcinogenesis

Activation of the Wnt pathway (primarily via APC mutation) or a mutation in BRAF can initiate colorectal tumorigenesis. BRAF mutations promote tumorigenesis via the serrated neoplasia pathway, leading to MSI with or without hypermutation (indicated in figure). Colorectal tumor classifications include CIN, MSI, and the serrated pathway (see CMS). L, low; H, high; EMT, epithelial to mesenchymal transition.

Figure 2.. MMR of Single-pair DNA Mismatches and Insertion or Deletion Loops

Upon detection of a DNA mismatch, MSH2 heterodimerizes with MSH6 or MSH3 to form MutSα (to correct single base-base or short insertion deletion loop mismatches) or MutSβ (principally to correct larger insertion deletion loop), respectively. These MutS complexes recognize the replication errors and form larger complexes, with MutL α, β, or γ (for example, MLH1 binds to PMS2, PMS1, or MLH3) to direct the action of exonuclease-1 and proliferating cell nuclear antigen (PCNA) and remove the misincorporated nucleotide(s). DNA polymerase and DNA ligase then reconstruct and reanneal the daughter strand to accurately reflect the parent strand.