Testing for deficient mismatch repair and microsatellite instability : A focused update

Area of Science:

• Oncology
• Molecular Diagnostics
• Cancer Research

Background:

• Mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) testing are integral to colorectal cancer (CRC) diagnostics.
• Initially linked to Lynch syndrome (LS), MSI testing is now pivotal for predicting response to immune checkpoint inhibitors (ICI).
• ICI therapies are expanding to non-CRC indications like endometrial, gastric, and biliary tract cancers, necessitating updated testing approaches.

Purpose of the Study:

• To provide an updated review of dMMR/MSI testing methods.
• To address challenges in assessing immunohistochemical (IHC) stains and the utility of PCR-based procedures.
• To offer a practice-oriented flowchart for diagnostic decision-making, considering discordant results and Next-Generation Sequencing (NGS).

Main Methods:

• Review of current literature and diagnostic guidelines for dMMR/MSI testing.
• Analysis of immunohistochemistry (IHC) and PCR-based methods for MSI detection.
• Evaluation of Next-Generation Sequencing (NGS) for clarifying discordant results.
• Inclusion of quality assurance measures and training recommendations.

Main Results:

• Updated recommendations and testing algorithms for primary CRC diagnosis are available.
• Challenges exist in assessing IHC stains, with PCR-based methods offering valuable insights.
• Discordances between MMR-IHC and MSI-PCR findings require careful consideration, with NGS as a potential clarifying tool.
• Systematic quality assurance and continuous training are essential for accurate dMMR/MSI testing.

Conclusions:

• dMMR/MSI testing is critical for both CRC diagnosis and guiding ICI therapy across various cancer types.
• A comprehensive approach integrating IHC, PCR, and potentially NGS is recommended for accurate assessment.
• Adherence to quality assurance protocols and ongoing education ensures reliable diagnostic outcomes.