Mismatch repair & microsatellite instability
After DNA is copied, a proofreading crew fixes the letters the polymerase got wrong. Lose it and the genome fills with thousands of small errors, especially in repetitive stretches (microsatellites). Those errors make abnormal proteins that the immune system can see, which is why immunotherapy works so well in these cancers.
MutSα (MSH2-MSH6) recognises base mismatches and small insertion-deletion loops, MutSβ (MSH2-MSH3) larger loops; MutLα (MLH1-PMS2) is recruited and nicks the new strand, EXO1 excises, Pol δ resynthesises, LIG1 seals. Loss of MLH1 (usually by promoter hypermethylation in sporadic colorectal and endometrial cancer, often with BRAF V600E), MSH2, MSH6 or PMS2 (germline in Lynch syndrome, or EPCAM deletion silencing MSH2) produces microsatellite instability (MSI-H), a hypermutator phenotype with 10-100x more mutations, frameshift neoantigens, and the SBS6/15/26 signatures. Clinically MSI-H/dMMR is tumour-agnostic for pembrolizumab and dostarlimab; dMMR rectal cancer can be cured with dostarlimab alone (complete responses in >90% of patients in the MSK study); neoadjuvant nivolumab-ipilimumab gives near-universal pathological responses in dMMR colon cancer. MMR loss also confers tolerance to temozolomide and thiopurines (the lesions are no longer recognised). Synthetic lethality: MSI-H cells depend on the WRN helicase; WRN inhibitors are in trials.
In one picture
A spell-checker that runs after every page is typed. Without it, typos pile up, especially in words like 'banana' where it is easy to lose count of the repeats. The garbled words in the resulting proteins read as foreign, so the immune system, once its brakes are released, attacks with unusual vigour.
Diagram
top- Tumour-agnostic pembrolizumab and dostarlimab for MSI-H/dMMR; nivolumab ± ipilimumab in colorectal cancer
- Organ-sparing: dostarlimab alone cures most dMMR rectal cancers; neoadjuvant nivolumab-ipilimumab in dMMR colon cancer
- Universal MMR/MSI testing of colorectal and endometrial cancer finds Lynch syndrome; colonoscopic surveillance and aspirin for carriers
- WRN helicase inhibitors as synthetic-lethal therapy for MSI-H tumours (trials)
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