Figure 3.

Progression of colorectal tumors with MSI. MSI tumors, whether sporadic or from patients with Lynch syndrome, lose MMR function early in the polyp → cancer progression sequence. Sporadic tumors almost uniformly lose MMR function due to hypermethylation of the promoter of hMLH1, whereas patients with Lynch syndrome have a germline mutation in one of the MMR genes. It is generally believed that Wnt signaling, the gatekeeper for colorectal neoplasia, is affected, but the full mechanisms are not clear and include mutation of CTNNB1, the gene encoding β-catenin in some cases of Lynch syndrome. The serrated adenoma may be one histologic form for MSI colorectal tumors. In the milieu of MMR absence, a hypermutable phenotype develops in which multiple mutations occur in DNA. Although most mutations occur in noncoding sequences such as intronic DNA microsatellites, certain genes such as TGFBR2, ACVR2, BAX, hMSH3, hMSH6, and others that have coding microsatellite sequences become frameshifted in the absence of DNA MMR. These mutations help drive the progression of the tumor. BRAF mutations are principally found in sporadic tumors with MSI and not tumors from patients with Lynch syndrome and can be used to differentiate these 2 groups of tumors. Notably, in MSI and non-MSI tumors, signaling through the TGF-β superfamily is altered to favor tumor promotion in a not yet fully understood fashion.