Lynch syndrome (hereditary non-polyposis colorectal cancer) results from germline mutations in DNA mismatch repair (MMR) genes. MSH2 and MLH1 account for the majority of cases. The consequence of defective MMR detectable in laboratory testing is:
- A Elevated chromosomal breakage on fragile sites
- B Microsatellite instability (MSI) in tumour DNA ✓
- C Large-scale chromosomal aneuploidies (CIN)
- D Elevated sister chromatid exchanges
Explanation
MMR proteins (MSH2/MSH6 form MutSalpha; MLH1/PMS2 form MutLalpha) recognise and repair base-base mismatches and insertion-deletion loops that arise during DNA replication, particularly in repetitive sequences called microsatellites. Loss of MMR leads to replication slippage errors going uncorrected, causing changes in the length of microsatellite repeats (microsatellite instability, MSI). Testing tumours for MSI (by PCR or immunohistochemistry for MMR protein loss) is used to screen for Lynch syndrome and to identify patients who may benefit from anti-PD-1 immunotherapy (pembrolizumab is approved for MMR-deficient/MSI-H tumours).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.