Definition
dMMR (deficient DNA mismatch repair) refers to loss of function in the DNA mismatch repair system, which normally corrects errors during DNA replication.
- Leads to microsatellite instability (MSI-H) and accumulation of mutations.
- Often seen in Lynch syndrome and some sporadic cancers.
Pathophysiology
- Normal MMR proteins: MLH1, MSH2, MSH6, PMS2
- Deficiency can occur via:
- Germline mutation (e.g., Lynch syndrome)
- Somatic mutations
- Epigenetic silencing (e.g., MLH1 promoter hypermethylation)
- Result: genomic instability, high mutational burden → tumorigenesis
Associated Cancers
- Colorectal cancer (CRC) – ~15%
- Endometrial cancer – ~20–30%
- Gastric cancer, ovarian cancer, and others
Clinical Significance
- Prognostic
- Early-stage dMMR colorectal cancers may have better prognosis.
- Predictive / Therapeutic Implications
- Immunotherapy (PD-1 inhibitors) is highly effective for dMMR/MSI-H tumors.
- dMMR tumors may be less responsive to fluoropyrimidine monotherapy in colorectal cancer.
Testing
- Immunohistochemistry (IHC): Loss of MMR protein expression
- PCR or NGS: Detects MSI-H phenotype
- Recommended for:
- All colorectal and endometrial cancers
- Patients suspected of Lynch syndrome
Pharmacy / Clinical Considerations
- Immunotherapy dosing:
- Pembrolizumab: 200 mg IV q3w or 400 mg q6w
- Nivolumab: 240 mg IV q2w or 480 mg q4w
- Monitor for immune-related adverse events (irAEs): colitis, hepatitis, pneumonitis, endocrinopathies
- May influence chemotherapy choices (avoid 5-FU monotherapy in stage II CRC if dMMR)
Prognosis
- Early-stage dMMR tumors → generally favorable prognosis
- Advanced/metastatic disease → benefit from checkpoint inhibitors