MSIhigh

MSIhigh, or microsatellite instability-high (MSI-H), refers to tumors that show a high level of instability at short repetitive DNA sequences called microsatellites due to deficiency in the DNA mismatch repair system (MMR). This instability drives an increased rate of genetic alterations across the genome.

Testing for MSI-H can be accomplished by molecular methods such as a PCR-based Bethesda/NCI panel that assesses instability at five microsatellite loci, or by broader next-generation sequencing approaches. Immunohistochemistry (IHC) can detect loss of MMR proteins—MLH1, MSH2, MSH6, and PMS2—indicating mismatch repair deficiency (dMMR). MSI-H is defined by instability at multiple loci or by loss of MMR protein expression.

MSI-H is most commonly detected in colorectal and endometrial cancers, but it also occurs in gastric, ovarian, pancreatic, and other tumor types. Causes include sporadic hypermethylation of the MLH1 promoter, other somatic alterations, or germline mutations in MMR genes as part of Lynch syndrome, an inherited cancer predisposition.

Clinically, MSI-H tumors often have a high tumor mutational burden and may respond well to immune checkpoint inhibitors, particularly PD-1–targeted therapies. Pembrolizumab, for example, is approved for treatment of MSI-H or MMR-deficient solid tumors regardless of tissue origin. MSI status also provides prognostic information that varies by cancer type and stage.

Limitations include discordant results between testing methods, nonresponse in some MSI-H cancers, and tumor heterogeneity. Testing for MSI-H/MMR status is recommended to guide therapy and to identify candidates for germline testing when Lynch syndrome is suspected.