Low microsatellite instability revisited: a review

Area of Science:

• Oncology
• Cancer Genomics
• Molecular Diagnostics

Background:

• Microsatellite instability (MSI), a marker of DNA mismatch repair deficiency, predicts response to immune checkpoint inhibitors.
• MSI-high (MSI-H) tumors are well-characterized, but low-level MSI (MSI-L) remains poorly understood and often grouped with microsatellite-stable (MSS) tumors.
• Emerging evidence suggests MSI-L may have distinct clinical and molecular features, particularly in gastric and colorectal cancers.

Purpose of the Study:

• To clarify the current understanding of MSI-L.
• To compare diagnostic methods for MSI-L classification.
• To explore potential mechanisms and therapeutic implications of MSI-L.

Main Methods:

• Review of diagnostic methods for MSI classification.
• Synthesis of clinical and molecular data on MSI-L in gastric and colorectal cancers.
• Analysis of emerging evidence on MSI-L mechanisms, including DNA damage tolerance pathways.

Main Results:

• MSI-L classification is influenced by diagnostic methods.
• MSI-L is associated with distinct clinical features, including prognosis and response to specific chemotherapies in gastric and colorectal cancers.
• Instability at dinucleotide repeats may define a specific MSI-L subset with unique molecular underpinnings.

Conclusions:

• MSI-L warrants further investigation beyond its current classification with MSS tumors.
• Specific MSI-L patterns, especially dinucleotide repeat instability, may indicate therapeutic vulnerabilities.
• Understanding MSI-L mechanisms, including DNA damage tolerance pathways, is crucial for its clinical application.