Microsatellite instability (MSI) is often discussed in the context of cancer. To better understand MSI, we first need to understand what microsatellites are. In genetics, microsatellites are a series of repeating nucleotides consisting of two to six bases. They are also called short tandem repeats (STRs) or simple sequence repeats (SSRs). These short nucleotide sequences are often repeated between 5 and 65 times at a particular genomic location. Microsatellites are distributed all over the genome, mostly in non-coding regions. As the number of repeated segments often varies between people, microsatellites can be helpful as DNA fingerprints for crime scene samples.
Mutations in microsatellites often lead to a gain or loss of one or even multiple repeat units. The actual cause of these mutations is still debated. The mutation rate at the microsatellite loci differs from other mutation rates and depends on the repeat sequence, the number of repeats, and the purity of the repeated sequence. It rises, especially with increasing repeat numbers. Usually, the DNA mismatch repair (MMR) system corrects errors that occur during DNA replication. Thus, with a functioning MMR system, mutations in microsatellites should be repaired. If the MMR system, however, does not function properly, the sequencing errors cannot be corrected adequately, and novel microsatellite fragments can occur.
As many tumor cells replicate rapidly, more sequencing errors can occur. If the MMR system is not functioning correctly, microsatellites can be gained or lost at a specifically high rate. This is then known as microsatellite instability. Thus, microsatellite instability can be used as an indirect detection method of problems or dysfunction in the MMR. This is particularly helpful, as the genes for the repair proteins are not clustered in so-called “hot spots”, making molecular genetic analysis difficult. Comparing the microsatellites from tumor cells and normal cells can give valuable insights into whether the MMR system is compromised in the tumor cells – and even one of the causative agents of cancer disease and tumor progression.
Three types of MSI are distinguished based on their frequency: high microsatellite instability (MSI-H), low microsatellite instability (MSI-L), and microsatellite stability (MSS). Patients with MSI-H tumors especially respond well to immunotherapy. Thus, determining a patient’s MSI status can provide valuable information for the proper treatment strategy.
Figure 1 | Microsatellite instability. Microsatellites, also called short tandem repeats (STRs), are a series of repeating nucleotides. The DNA mismatch repair (MMR) system, responsible for repairing errors arising from DNA replication, can repair replication errors in microsatellites. If the MMR system cannot correctly repair these errors, microsatellite instability occurs, resulting in variable allele sizes.