Lynch syndrome - mismatch repair deficiency and microsatellite instability
Core concept
- Autosomal dominant germline mutation in a mismatch repair gene: MLH1, MSH2, MSH6, PMS2 (+ EPCAM deletion silencing MSH2)
- MMR normally corrects base-base mismatches and insertion-deletion loops made by polymerase slippage in repetitive DNA
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Germline MMR variant + somatic second hit
- dec MMR
- -> replication errors accumulate in microsatellites
- -> MSI-high, tumour mutational burden very high
- -> frameshift neoantigens -> dense T-cell infiltrate
- -> immune checkpoint inhibitor sensitivity
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- Microsatellite = short tandem repeat (mono-/di-nucleotide); instability = a change in repeat length in tumour vs normal DNA
- Commonest hereditary colorectal cancer syndrome (~3% of all CRC), and the commonest cause of hereditary endometrial cancer
3 more sections, plus exam facts
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