Fig. 5.

An integrated model for different forms of genetic and epigenetic instability in CRC. Tumors can develop via chromosomal instability (CIN), microsatellite instability (MSI), or CpG island methylator phenotype (CIMP) pathways. MSI may develop either from Lynch syndrome (the hereditary form), or via the CIMP pathway (a presumably acquired form). Ultimately, all pathways converge pathologically as cancer. Based upon our current understanding, CIN and CIMP represent the two primary processes of genetic and epigenetic instability respectively, in the colon. In essence, MSI in sporadic CRCs originates because of CIMP, and once MLH1 becomes methylated, the tumors acquire MSI. Thus far the molecular mechanisms for CIN and CIMP are not clear, however, there are data to suggest that JC virus (JCV) may be a putative unifying mechanism for genetic and epigenetic instability in CRC.

CRC, colorectal cancers; MMR, mismatch repair.