Definition
- MMR (Mismatch Repair) is a cellular DNA repair system that corrects errors during DNA replication, such as base-base mismatches and insertion/deletion loops.
- Key proteins: MLH1, MSH2, MSH6, PMS2
2. MMR Deficiency vs Proficiency
| Term | Meaning | Clinical Significance |
|---|---|---|
| MMR-Proficient (pMMR) | All MMR proteins functional | Microsatellite stable (MSS); standard prognosis and treatment |
| MMR-Deficient (dMMR) | Loss of ≥1 MMR protein | Leads to microsatellite instability-high (MSI-H), genomic hypermutability; associated with Lynch syndrome in some cases |
3. Detection Methods
- Immunohistochemistry (IHC): Detects loss of MMR protein expression
- PCR / NGS for MSI testing: Detects microsatellite instability
- Interpretation:
4. Clinical Implications in Oncology
- dMMR/MSI-H tumors:
- ~15% of sporadic CRC
- Poor response to fluoropyrimidine monotherapy in stage II
- Better prognosis in early-stage disease
- Screening for Lynch syndrome: dMMR in young patients or family history → refer for genetic counseling
- pMMR/MSS tumors: standard adjuvant therapy applies
- dMMR/MSI-H tumors across tumor types → high mutational burden → responsive to immune checkpoint inhibitors
- Examples: pembrolizumab, nivolumab
- pMMR/MSS tumors → usually less responsive to immunotherapy
C. Other Cancers
- Endometrial cancer: ~20–30% dMMR
- Gastric, pancreatic, prostate, and others: subset may be dMMR/MSI-H → candidate for immunotherapy
5. Key Points for Oncology Pharmacists
- Always check MMR/MSI status in newly diagnosed CRC (and some other cancers).
- dMMR/MSI-H → consider immunotherapy in advanced/metastatic settings.
- pMMR/MSS → standard chemotherapy regimens.
- dMMR in early-stage CRC: may avoid fluoropyrimidine monotherapy for stage II.
- Genetic counseling if patient is young or family history is significant → screen for Lynch syndrome.