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Tests that show whether a tumour has lost its DNA spell-checker; if so, immunotherapy works unusually well and an inherited syndrome may be present.
Mismatch-repair deficiency is detected by immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 (loss of any protein), by PCR for microsatellite instability at five or more markers (MSI-high), or by NGS-based MSI calling in panels such as FoundationOne CDx and TSO Comprehensive. In 2017 pembrolizumab became the first tissue-agnostic approval on the basis of MSI-high or dMMR status, and dostarlimab followed in dMMR endometrial cancer with the VENTANA MMR RxDx companion panel (2021). Universal testing of all colorectal and endometrial cancers is recommended both to guide immunotherapy and to screen for Lynch syndrome, with MLH1 promoter methylation and BRAF V600E testing used to separate sporadic from inherited cases. Roughly 15% of colorectal, 25-30% of endometrial and smaller fractions of gastric and other cancers are dMMR.
Loss of mismatch repair leaves insertion-deletion errors at repetitive microsatellite sequences; the protein loss, the instability, or the resulting hypermutation can each be measured.
A four-stain test that shows whether a womb cancer has lost its DNA spell-checker, which makes immunotherapy likely to work.
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.
MSI testing has a very low yield in TNBC; TMB and PD-L1 are the immunotherapy biomarkers worth pursuing.
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 fixed the working numbers for a comprehensive panel in pancreatic cancer: a hit worth acting on in about one patient in six, most of it in repair genes and the KRAS wild-type minority.
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.
Query for this technology: (TITLE:"MSI and mismatch-repair testing" OR ABSTRACT:"MSI and mismatch-repair testing") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about MSI and mismatch-repair testing, not a curated reading list.
Shares Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients, Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, 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.
Shares Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients, Deficient mismatch repair system in patients with sporadic advanced colorectal cancer, Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.
Shares Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients, Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, Mismatch repair status and BRAF mutation status in metastatic colorectal cancer: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies, Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142).
Shares Deficient mismatch repair system in patients with sporadic advanced colorectal cancer, Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, 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.
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, Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations.
Shares Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations, Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers, Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR).
Shares Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers, FoundationOne CDx / Liquid CDx, Diagnostics roadmap: stains → gene panels → blood tests that decide treatment, Companion diagnostics.
Shares Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency, Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval, KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer, Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ.
Open-source projects that implement or serve this technology, from OnCo's own catalogue: licence and last activity as the repository reported them on the day of the fetch. Listing is not endorsement; check the licence before reuse and the validation before clinical use.
Turns a tumour's somatic variant calls into an interpreted clinical report: driver annotation, actionability tiers, tumour mutational burden, MSI and mutational signatures.
The original microsatellite instability caller for paired tumour-normal sequencing from the Ding lab.
Detects microsatellite instability from tumour sequencing, with a tumour-only mode that needs no matched normal.
Microsatellite instability detection from tumour-normal sequencing, designed for targeted panels.