A 28-year-old woman with Lynch syndrome (HNPCC) carries a germline mutation in MLH1. This gene encodes a mismatch repair (MMR) protein. Which type of mutation is most uniquely generated when MMR is defective, and what is the molecular signature it creates?

• A Tandem duplications at palindromic sequences; detected as copy number variation on SNP array
• B Insertion-deletion loops at microsatellite repeats, causing microsatellite instability (MSI) ✓
• C CC→TT transitions at dipyrimidine sites, causing UV-signature mutations
• D G→T transversions from oxidized guanine (8-oxoguanine) mispairing with adenine

Explanation

MMR corrects single-base mismatches and small insertion-deletion loops (IDLs) that arise particularly at microsatellite repeat sequences during replication. When MMR is defective (MLH1, MSH2, MSH6, PMS2 mutations), replication slippage at microsatellites generates uncorrected IDLs, causing allele size variation called microsatellite instability (MSI). MSI-High is the hallmark of Lynch syndrome-associated colorectal, endometrial, and other cancers. This is also detected as loss of mismatch repair (dMMR) on immunohistochemistry, directing therapy with immune checkpoint inhibitors.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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