Mismatch repair deficiency (MMRd) is caused by the biallelic inactivation of an MMR gene, which can be attributed either to an inherited or an acquired pathway. MMRd is characterized by the inability of cells to repair spontaneous mutations in microsatellites that occur during replication. Microsatellites are repetitive nucleotide sequences composed of one to six base pairs. Mutations in microsatellites lead to deletions or insertions of sequence units that are designated as microsatellite instability (MSI). MMRd is diagnosed by immunochemistry and is characterized by loss of nuclear immunostaining for at least one of the four MMR proteins that are routinely examined, i.e., MSH2, MSH6, MLH1 and PMS2. Available tests for MSI are PCR and next generation sequencing. MMRd and MSI predispose to tumor initiation and progression, increase tumor mutational burden as well as tumor immunogenicity, facilitate the activation of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway and serve as prognostic and predictive biomarkers in solid tumors.
- biomarkers
- immune checkpoint inhibition
- immunohistochemistry
- mismatch repair proficiency
- mismatch repair deficiency
- microsatellites
- microsatellite instability
- next generation sequencing
- PCR
This entry paper provides a comprehensive overview of the impact of mismatch repair deficiency (MMRd) and microsatellite instability (MSI) on tumor initiation and progression as well as the relevance of these alterations as diagnostic, prognostic and predictive biomarkers. In this regard, it highlights the gain in medical importance that both markers have received from the initial discovery of their causative role in Lynch syndrome until nowadays, where they influence prognostic and therapeutic decisions for Lynch syndrome-associated and sporadic tumors. It also provides guidance for the diagnostic evaluation of MMRd and MSI in different cancer types and explains the limitations of routinely available tests. Thereby, it identifies the immediate need for improved MSI detection across different cancer types and provides research guidance by summarizing recent scientific studies in this field. The development of standardized tests to detect MSI with high sensitivity and specificity in non-colorectal cancers will likely not only improve prognostic evaluation and treatment success of different tumor entities but may also help to identify additional therapeutic options.