Qualitative and Quantitative Aspects of Discrepancies between Various Methods for Microsatellite Instability Detection

The discordance rate of the results between immunohistochemistry (IHC) and molecular microsatellite instability (MSI-PCR) tests, the most commonly used methods for qualitative deficient mismatch repair (dMMR) testing, is 1–10%, highlighting the need for a more precise testing strategy. The next-generation sequencing (NGS) offers a more sensitive and effective dMMR analysis (MSI-NGS), which also provides quantitative data. The aim of the study was to evaluate the qualitative and quantitative aspects of IHC and MSI-PCR testing compared to MSI-NGS in detecting dMMR in patients with Lynch Syndrome (LS)-associated and sporadic colorectal (CRC) and endometrial cancers (EC). Our results demonstrate both qualitative and quantitative discrepancies in the results obtained with different methods. Regarding qualitative differences, dMMR was inadequately interpreted only in LS when relying solely on IHC or MSI-PCR testing. This was primarily due to the specific mutational profile in our population, indicating the need for the implementation of a specific strategy that combines both methods. Concerning the quantitative differences, we detected great variability in the MSI levels, which was partly attributed to the tissue type or to the type of mutation in LS patients. Our results suggest that MSI-NGS level could be used as a potential surrogate marker for neoantigen levels and provide more precise predictive information for immunotherapy in patients with dMMR deficiency.