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Microsatellite instability is the mark of a broken DNA spell-checker (loss of MLH1, MSH2, MSH6 or PMS2) that leaves thousands of mutations, so the tumour displays abnormal proteins that T cells can recognise. It is found in a fraction of colorectal and endometrial cancers and was the basis of the first tumour-agnostic approval, pembrolizumab in 2017.
Microsatellite instability (MSI-H), or mismatch repair deficiency (dMMR), is the mark of a broken DNA spell-checker: loss of MLH1, MSH2, MSH6 or PMS2, through Lynch syndrome or sporadic MLH1 methylation, creates thousands of mutations and makes the tumour recognisable to T cells and therefore responsive to immunotherapy. It is found in a meaningful fraction of Colorectal cancer and Endometrial cancer. Pembrolizumab in MSI-H disease was the first tumour-agnostic approval, in 2017, and Dostarlimab achieves complete responses in dMMR rectal cancer without surgery. The biomarker is central to the KEYNOTE-177, CheckMate 8HW, NICHE-2, ATOMIC, AZUR-1 and RUBY trials and to the pairing of neoadjuvant checkpoint inhibitor with surgery or no surgery in dMMR colorectal cancer.
Backbone ribbon from PDB 5DK3. RCSB PDB 5DK3. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Showing the molecule this term concerns: Pembrolizumab.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
The 48 most recent of 50 papers; see them all →
HER2 is as frequent in India as in the West, so HER2 testing pays off in the highest-incidence population, while tumour-agnostic immunotherapy markers will rarely apply. The paper also shows plasma testing is feasible where tissue is scarce.
For mismatch repair-deficient rectal cancer, six months of a single antibody now replaces chemotherapy, radiotherapy and an operation, and the same appears to be true for early-stage mismatch repair-deficient cancers of other organs.
The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare.
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.
Combination checkpoint blockade became a first-line standard for mismatch repair-deficient metastatic colorectal cancer in 2025; the later all-lines comparison against nivolumab alone showed the CTLA-4 antibody adds to the PD-1 antibody, the first phase 3 to prove that in this disease.
This is the European standard the UK and NHS page for colorectal cancer is compared against; NICE NG151 covers the same ground for England with a narrower set of funded drugs.
A UK-led trial that moved part of colon cancer chemotherapy in front of the operation, and showed that tumour regression grade after six weeks predicts recurrence, which is the basis for using the response itself to choose what follows.
Women with newly diagnosed advanced or recurrent endometrial cancer should receive a PD-1 antibody (dostarlimab or pembrolizumab) with their chemotherapy, and mismatch repair testing is now essential because women with dMMR tumours gain a very large and durable benefit. The gain in mismatch-repair-proficient tumours is real but smaller, and molecular classification (POLE, p53, MMR) is increasingly used to decide who benefits most.
Shares Aurélien Marabelle, Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets, Genomic correlates of immune-cell infiltrates in colorectal carcinoma, Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer.
Shares HER2 and genomic testing for biliary cancer on the NHS, A standard for tumour-agnostic approvals: minimum histologies and hierarchical modelling, WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers, KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer.
Shares Aurélien Marabelle, CAVE mCRC, Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability, IMblaze370.
Shares International validation of the consensus Immunoscore for the classification of colon cancer, The pathology lab triggers a trial referral the day a rare cancer is diagnosed, Deficient mismatch repair system in patients with sporadic advanced colorectal cancer, Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability.
Shares Nouscom, Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability, Genomic correlates of immune-cell infiltrates in colorectal carcinoma, A frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval.
Shares Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features, Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia, A standard for tumour-agnostic approvals: minimum histologies and hierarchical modelling, The serrated pathway to colorectal carcinoma: current concepts and challenges.
Shares Deficient mismatch repair system in patients with sporadic advanced colorectal cancer, CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer, Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma, Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines.
Shares Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer, MSH2 loss in primary prostate cancer, Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines, Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations.