MMRsilencing

MMR silencing refers to the epigenetic or transcriptional downregulation of DNA mismatch repair (MMR) genes, most commonly through promoter hypermethylation, which reduces or abolishes expression of MMR proteins such as MLH1, MSH2, MSH6, and PMS2. This silencing impairs the cell’s ability to correct DNA replication errors, often leading to a microsatellite instability (MSI) phenotype characterized by increased mutation risk in repetitive DNA sequences.

The primary mechanism in sporadic cancers is MLH1 promoter methylation, though other epigenetic changes and less commonly promoter methylation of other MMR genes can contribute. In hereditary contexts, such as Lynch syndrome, germline mutations in MMR genes cause deficient MMR independently of methylation. MMR silencing can therefore arise from a combination of genetic and epigenetic alterations that reduce MMR protein activity.

Detection and characterization typically involve immunohistochemistry to assess the presence of MMR proteins, MSI testing by PCR to identify MSI-H (high-level MSI) status, and methylation analyses to detect promoter methylation, especially of MLH1. The pattern of protein loss, MSI status, and methylation helps distinguish sporadic MMR silencing from germline causes requiring genetic counseling.

Clinical significance includes implications for prognosis and treatment. MSI-H tumors with MMR silencing often respond better to immune checkpoint inhibitors and may have distinct clinical features compared with MMR-proficient tumors. MLH1 promoter methylation in colorectal and other cancers frequently indicates a sporadic origin rather than Lynch syndrome, guiding genetic testing and management decisions. Ongoing research explores reversal of silencing and broader implications for cancer therapy.