Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers

Abstract

Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the sensitivity to immune checkpoint inhibitors (ICIs), particularly PD1/PD-L1 inhibitors. To date, the predictive role of MSI is currently used in the selection of colorectal cancer patients for immunotherapy; moreover, the expansion of clinical trials into other cancer types may elucidate the predictive value of MSI for non-colorectal tumors. In clinical practice, several assays are used for MSI testing, including immunohistochemistry (IHC), polymerase chain reaction (PCR) and next-generation sequencing (NGS). In this review, we provide an overview of MSI in various cancer types, highlighting its potential predictive/prognostic role and the clinical trials performed. Finally, we focus on the comparison data between the different assays used to detect MSI in clinical practice.

Keywords: NGS; PCR; immunohistochemistry; immunotherapy; microsatellite instability; mismatch repair.

Figure 1

Frequency of microsatellite instability in gastrointestinal and gynecologic cancers. Distribution of MSI according to the molecular classification of colorectal cancer, gastric cancer, ovarian and endometrial cancers. CIN: chromosome instability; CIMP: CpG island methylator phenotype; MSI: microsatellite instability; EBV: Epstein–Barr virus; GS: genomically stable; NSMP: no specific molecular profile; POLE: DNA polymerase epsilon.

Figure 2

The diagnostic algorithm of MSI status. MMRP IHC is used as a screening test: the intact expression of all four MMRPs is a conclusive result of the MSS status (original magnification 10×); the heterogeneous staining of one or more MMRPs needs an additional molecular assay (original magnification 10×); and the loss of one or more MMRPs needs a molecular assay (original magnification 10×). The molecular analysis performed through PCR and/or NGS leads to a conclusive result in cases with IHC equivocal staining. MMRP: mismatch repair proteins; IHC: immunohistochemistry; PCR: polymerase chain reaction; NGS: new-generation sequencing; MSS: microsatellite stability; MSI-L: microsatellite instability-low; MSI-H: microsatellite instability-high. The stars indicate the PMS2 heterogeneous staining (center) and the loss of MLH1 and PMS2 (right).