DNA mismatch repair is a process cells use to identify and repair mismatched bases in DNA strands. Such mismatches may occur during DNA replication, genetic recombination, or chemical or physical damage. In the illustration shown here, the guanine base (G) is inappropriately matched with a thymine base (T). Through a complex mechanism involving the formation of several protein complexes, the damaged DNA is removed and replaced by a strand that has the appropriate base match. The genes that code for these protein complexes include MLH1, MSH2, MSH6, and PMS2.

High-frequency microsatellite instability (MSI-H) is associated with defective function of the DNA mismatch repair system. This may occur in patients with Lynch syndrome, which is characterized by inherited mutations in the MLH1, MSH2, MSH6, and PMS2 genes. Alternatively, MSI-H may arise sporadically due to hypermethylation of the MLH1 gene promoter, which effectively silences the gene. The latter mechanism is associated with several clinicopathological features, including BRAF mutations. BRAF mutations are almost never seen in patients with Lynch syndrome.

IHC tests for dMMR and DNA analysis for MSI are different assays measuring the same biological effect. The presence of MSI-H in early stage disease is associated with a good prognosis, possibly due to an enhanced immune response. In more advanced disease, MSI-H is sometimes associated with BRAF mutations, which counteract this favorable prognosis. Research has shown MSI-H disease may not respond to 5-FU therapy as well as microsatellite-stable (MSS) disease, but may have an improved response to immunotherapies.