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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.
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.
For colon cancer that is mismatch-repair deficient (about 10-15% of colon cancers, more in older patients), a single short course of immunotherapy before surgery is now a reasonable standard and is far more effective than chemotherapy, which has little effect in this subtype. It requires testing every colon cancer for mismatch repair at diagnosis, before surgery. Whether some patients can safely skip surgery, as in dMMR rectal cancer, is the next question.
Cercek's dostarlimab study is the clearest demonstration that immunotherapy can replace surgery in a solid tumour: patients with dMMR rectal cancer can keep their rectum and avoid the permanent effects of pelvic radiotherapy and surgery. Non-operative management after PD-1 blockade is now in guidelines for this group, and MMR testing before treatment of rectal cancer is essential. The approach applies only to the 5-10% of rectal cancers that are dMMR.
It tells the pathologist which pancreatic cancers to test for the one immunotherapy-responsive subgroup and how.
Every colorectal cancer should be tested for mismatch repair deficiency, because patients whose metastatic tumour is dMMR should receive pembrolizumab rather than chemotherapy as first treatment, gaining a much better chance of durable remission with fewer side effects. About a third of dMMR tumours do not respond initially, so early scans are essential and chemotherapy remains available. The trial does not apply to the 95% of metastatic colorectal cancers that are mismatch-repair proficient (the deficient share is higher in localised disease, about 15%).
It is the second half of the argument for unselected germline testing, and it widens the target beyond BRCA: two thirds of the actionable inherited findings in prostate cancer are in other genes, including the mismatch repair genes that open a checkpoint inhibitor route.
It is the argument for sequencing every man with advanced prostate cancer rather than only the ones who look high risk: the phenotype is uncommon, it is invisible clinically, it opens the only durable immunotherapy route in this disease, and in one man in five it also identifies Lynch syndrome in the family.
Guidelines recommending universal mismatch repair testing in pancreatic cancer, by immunohistochemistry or sequencing rather than PCR alone, rest on this and similar series.
This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.
Shares Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer, MSH2 loss in primary prostate cancer, Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade, NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients and the tags mechanism, mechanics-atlas.
Shares Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines, Synthetic lethality: paired dependencies, Mutagenesis & mutational signatures, Mutational signature and the tags mechanism, mechanics-atlas.
Shares Antigen presentation & immune editing, CTLA-4, PD-1 / PD-L1 immune checkpoint & T-cell activation, PD-L1 and the tags mechanism, mechanics-atlas.
Shares Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, Tumour mutational burden (TMB), PD-L1, PD-1 and the tags mechanism, mechanics-atlas.
Shares Mutagenesis & mutational signatures, Synthetic lethality approaches, Germline (hereditary) testing, Comprehensive genomic profiling and the tags mechanism, mechanics-atlas.
Shares Synthetic lethality: paired dependencies, Synthetic lethality approaches, Germline (hereditary) testing, Comprehensive genomic profiling and the tags mechanism, mechanics-atlas.
Shares EpCAM, Aspirin for cancer prevention and adjuvant therapy, Prostate cancer and the tags mechanism, mechanics-atlas.
Shares The consensus molecular subtypes of colorectal cancer, PD-1, Pancreatic ductal adenocarcinoma, Colorectal cancer and the tags mechanism, mechanics-atlas.