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

Area of Science:

• Oncology
• Molecular Diagnostics
• Genetics

Background:

• Immunohistochemistry (IHC) and microsatellite instability-PCR (MSI-PCR) are standard for deficient mismatch repair (dMMR) testing but show 1-10% discordance.
• Next-generation sequencing (NGS) provides sensitive, quantitative MSI analysis (MSI-NGS) for dMMR detection.

Purpose of the Study:

• To compare qualitative and quantitative dMMR detection using IHC, MSI-PCR, and MSI-NGS.
• To evaluate these methods in Lynch Syndrome (LS)-associated and sporadic colorectal (CRC) and endometrial cancers (EC).

Main Methods:

• Comparative analysis of IHC, MSI-PCR, and MSI-NGS for dMMR testing.
• Assessment of qualitative and quantitative results across different cancer types and patient cohorts.

Main Results:

• Significant qualitative and quantitative discrepancies were observed between the methods.
• IHC and MSI-PCR alone inadequately detected dMMR in LS patients due to specific mutational profiles.
• MSI-NGS revealed variability in MSI levels influenced by tissue type and mutation in LS patients.

Conclusions:

• A combined strategy of IHC and MSI-PCR may be necessary for accurate dMMR interpretation in LS.
• MSI-NGS offers a more precise dMMR analysis and may serve as a surrogate marker for neoantigen levels.
• MSI-NGS quantitative data could enhance immunotherapy prediction in dMMR-deficient cancers.