Microsatellite instability

Microsatellite instability (MSI) is the condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair (MMR).

MMR corrects errors that spontaneously occur during DNA replication, such as single base mismatches or short insertions and deletions.

[3] Although researchers do not agree on a specific threshold for the number of tandem repeats that constitute a microsatellite, there is a consensus around their relative size.

In a broad sense, MSI results from the inability of the mismatch repair (MMR) proteins to fix a DNA replication error.

Hypermethylation occurs when a methyl group is added to a DNA nucleotide, resulting in gene silencing, thus yielding MSI.

[3] One study conducted over 120 Lynch syndrome patients attributing Crohn's like reaction (CLR) associated with MSI to "tumor specific neopeptides generated during MSI-H carcinogenesis."

This study further corroborated that the "presence of antimetastatic immune protection in MSI-H CRC patients may explain recent findings that adjuvant 5-FU chemotherapy has no beneficial or even adverse effects in this collective."

[15] In May 2017 the FDA approved an immunotherapeutic called Keytruda (pembrolizumab) (PD-1 inhibitor) for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment.

In 1996, the National Cancer Institute (NCI) hosted an international workshop on Lynch Syndrome, which led to the development of the "Bethesda Guidelines" and loci for MSI testing.

During this first workshop the NCI has agreed on five microsatellite markers necessary to determine MSI presence: two mononucleotides, BAT25 and BAT26, and three dinucleotide repeats, D2S123, D5S346, and D17S250.

[3] Six years later, during the second NCI hosted workshop to revisit Lynch Syndrome in 2002, the Bethesda Guidelines were revised (later published in 2004[17]) which recommended new criteria for MSI testing.

The first commercially available kit was provided by Promega Corporation, Madison, Wisconsin called the Microsatellite Instability 1.2 Analysis System (RUO).

[12][19] Digital pathology can be submitted to machine learning techniques and predictions about MSI can be made without any molecular testing.

The NER DNA repair pathway plays a substantial role in reversing cell damage caused by chemotherapeutic agents such as 5-FU.

[20] It has been shown that MSI-H cancers are dependent on the Werner syndrome helicase (WRN) to repair the DNA secondary structures that are formed by expanded TA microsatellites.

[9] Because of this targeted therapeutic hypothesis, inhibition of WRN has become an area of high interest for the treatment of MSI-H malignancies.

[24] In May 2017 the FDA approved an immunotherapeutic called Keytruda (pembrolizumab) (PD-1 inhibitor) for patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment.

[16] Researchers have found another MSI, called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST).

[5] EMAST is seen in a variety of cancers including those of the lung, head and neck, colorectal, skin, urinary tract, and the reproductive organs.