{"entity":{"id":"msi-mmr-testing","kind":"technology","name":"MSI and mismatch-repair testing","aka":[],"tldr":"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.","summary":"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.","status":"standard-of-care","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Microsatellite_instability","links":[{"label":"FDA: pembrolizumab tissue-agnostic approval for MSI-H/dMMR tumours (2017) (archived copy)","url":"https://web.archive.org/web/20260420012135/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication"},{"label":"Macmillan: tests on the bowel cancer cells","url":"https://www.macmillan.org.uk/cancer-information-and-support/bowel-cancer/tests-on-the-bowel-cancer-cells"},{"label":"NICE NG151: colorectal cancer, recommendations","url":"https://www.nice.org.uk/guidance/ng151/chapter/Recommendations"},{"label":"Bowel Cancer UK: Lynch syndrome","url":"https://www.bowelcanceruk.org.uk/campaigning/never-too-young/lynch-syndrome/"}],"tags":[],"related":[],"cancers":["colorectal","endometrial","gastric"],"sections":["diagnostics"],"technologies":["histopathology-ihc","companion-diagnostic","germline-testing"],"targets":[],"drugs":["pembrolizumab","dostarlimab","ventana-mmr-rxdx","foundationone-cdx"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","mss-pmmr","lynch-syndrome","tmb"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-moreira-lynch-syndrome-identification-jama-2012","paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017"],"journals":[],"dependsOn":[],"notes":["Bowel cancer: the mismatch repair or microsatellite instability result does three jobs at once. It opens the door to immunotherapy (NICE NG151 recommends nivolumab with ipilimumab and pembrolizumab for untreated metastatic disease that is MSI-high or mismatch repair deficient), it starts the Lynch syndrome pathway when repair proteins are lost, and it feeds the conversation about chemotherapy after surgery. NICE NG151 separately requires RAS and BRAF V600E testing in everyone with metastatic disease suitable for systemic treatment.","Colorectal cancer: this is the test that colorectal practice is built around. Universal four-protein immunohistochemistry on every tumour found 100% of Lynch syndrome carriers against 87.8% for the Bethesda guidelines (Moreira 2012), and the same result selects immunotherapy. The reflex step is what separates the two causes: MLH1 loss prompts BRAF V600E or MLH1 promoter methylation testing, because the sporadic route is CIMP-associated silencing rather than a germline variant (Herman 1998, Weisenberger 2006). It does not see POLE-ultramutated tumours, which are microsatellite stable (Domingo 2016)."],"principle":"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.","strengths":["Cheap immunohistochemistry available everywhere","Identifies the most immunotherapy-responsive tumours","Doubles as Lynch syndrome screening"],"limitations":["Immunohistochemistry can be misleading with missense variants that preserve protein","Immunotherapy still fails in about a third of dMMR tumours","Germline confirmation needs a separate blood test"]},"route":"/technologies/msi-mmr-testing/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"lynch-associated-colorectal-cancer","kind":"cancer","name":"Lynch syndrome-associated colorectal cancer","route":"/cancers/lynch-associated-colorectal-cancer/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"}],"technology":[{"id":"companion-diagnostic","kind":"technology","name":"Companion diagnostics","route":"/technologies/companion-diagnostic/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"}],"drug":[{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/"},{"id":"foundationone-cdx","kind":"drug","name":"FoundationOne CDx / Liquid CDx","route":"/drugs/foundationone-cdx/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"ventana-mmr-rxdx","kind":"drug","name":"VENTANA MMR RxDx Panel","route":"/drugs/ventana-mmr-rxdx/"}],"term":[{"id":"cimp","kind":"term","name":"CpG island methylator phenotype (CIMP)","route":"/terms/cimp/"},{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"lynch-syndrome-testing-uk","kind":"term","name":"Lynch syndrome testing after bowel cancer, and what it means for the family","route":"/terms/lynch-syndrome-testing-uk/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"mss-pmmr","kind":"term","name":"Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)","route":"/terms/mss-pmmr/"},{"id":"mlh1-promoter-methylation","kind":"term","name":"MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)","route":"/terms/mlh1-promoter-methylation/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"paper":[{"id":"paper-cercek-dostarlimab-rectal-nejm-2022","kind":"paper","name":"Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency","route":"/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/"},{"id":"paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","kind":"paper","name":"Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications","route":"/key-papers/paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021/"},{"id":"paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","kind":"paper","name":"CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer","route":"/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/"},{"id":"paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009","kind":"paper","name":"Deficient mismatch repair system in patients with sporadic advanced colorectal cancer","route":"/key-papers/paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009/"},{"id":"paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","kind":"paper","name":"Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations","route":"/key-papers/paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018/"},{"id":"paper-moreira-lynch-syndrome-identification-jama-2012","kind":"paper","name":"Identification of Lynch syndrome among patients with colorectal cancer","route":"/key-papers/paper-moreira-lynch-syndrome-identification-jama-2012/"},{"id":"paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","kind":"paper","name":"Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma","route":"/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/"},{"id":"paper-keynote-177-nejm-2020","kind":"paper","name":"KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer","route":"/key-papers/paper-keynote-177-nejm-2020/"},{"id":"paper-le-mmr-deficiency-pd1-nejm-2015","kind":"paper","name":"Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ","route":"/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/"},{"id":"paper-le-mmr-deficiency-science-2017","kind":"paper","name":"Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval","route":"/key-papers/paper-le-mmr-deficiency-science-2017/"},{"id":"paper-ren-tnbc-mmr-msi-440-front-oncol-2021","kind":"paper","name":"Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients","route":"/key-papers/paper-ren-tnbc-mmr-msi-440-front-oncol-2021/"},{"id":"paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014","kind":"paper","name":"Mismatch repair status and BRAF mutation status in metastatic colorectal cancer: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies","route":"/key-papers/paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014/"},{"id":"paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017","kind":"paper","name":"Molecular biomarkers for the evaluation of colorectal cancer: guideline from ASCP, CAP, AMP and ASCO","route":"/key-papers/paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017/"},{"id":"paper-niche-2-nejm-2024","kind":"paper","name":"NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients","route":"/key-papers/paper-niche-2-nejm-2024/"},{"id":"paper-overman-checkmate-142-nivolumab-dmmr-colorectal-lancet-oncol-2017","kind":"paper","name":"Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142)","route":"/key-papers/paper-overman-checkmate-142-nivolumab-dmmr-colorectal-lancet-oncol-2017/"},{"id":"paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","kind":"paper","name":"Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers","route":"/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/"}],"roadmap":[{"id":"diagnostics-roadmap","kind":"roadmap","name":"Diagnostics roadmap: stains → gene panels → blood tests that decide treatment","route":"/roadmaps/diagnostics-roadmap/"}]}}