Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer

Figure 1 Human DNA mismatch repair. A: Two DNA recognition complexes MutSα, which recognizes insertion-deletion (I/D) loops of 1-2 repeated nucleotides for repair, and MutSβ which recognizes I/D loops of 2 or greater nucleotides for repair, are the key protein complexes of MMR. The MLH1 and PMS2 complex, also known as MutLα, then helps execute the repair with the exonuclease Exo1, polymeraseβ and DNA ligase to fully effect repair; B: Specific efficiency in one of the five DNA MMR proteins yields differing microsatellite instability (MSI) results. Loss of MLH1, MSH2 or PMS2 will yield frameshifts at mono-, di- and tetra-nucleotide microsatellite markers. Loss of MSH6, inactivating MutSα only, will yield mononucleotide mostly but some dinucleotide microsatellite frameshifts, whereas loss of MSH3, inactivating MutSβ, will yield di- and tetranucleotide microsatellite frameshifts, but no mononucleotide microsatellite frameshifts; C: Examples of fragment analysis comparing normal colon tissue (upper panels) with tissue (lower panels) demonstrating frameshifts in the tetranucleotide marker D20S82. MMR: Mismatch repair; MSI: Microsatellite instability; CRC: Colorectal cancer.

Figure 2 MSH3 expression in sporadic colorectal cancer. A: Immunohistochemistry for MSH3 in sporadic CRC. Arrows show heterogeneous expression of MSH3 in cells and within nuclei in the epithelium; B: Model of MSH3 displacement from the nucleus to the cytosol with inflammatory stimuli to allow accumulation of tetranucleotide frameshift mutations. Progenitor cells could be affected earlier such that subsequent daughter cells amplify the accumulated frameshift mutations. MSI: Microsatellite instability; CRC: Colorectal cancer; EMAST: Elevated microsatellite alterations at selected tetranucleotide repeats.

Figure 3 Model of adenoma-to-carcinoma formation in the human colon, with actual and potential sites of interventions to improve survival. MSI: Microsatellite instability; CRC: Colorectal cancer; EMAST: Elevated microsatellite alterations at selected tetranucleotide repeats.