{"entity":{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","aka":["dMMR","MMR-deficient","mismatch repair deficient","MMRd","loss of MLH1","loss of MSH2","loss of MSH6","loss of PMS2","MMR IHC","MMR protein loss"],"tldr":"dMMR means one of the four mismatch repair proteins is missing from the tumour cell nuclei on a stain. It is the tissue-level twin of MSI-high and opens checkpoint immunotherapy in endometrial, bowel and many other cancers.","summary":"Immunohistochemistry for MLH1, PMS2, MSH2 and MSH6 is read as retained or lost nuclear staining in tumour cells against an internal positive control; loss of any protein is mismatch repair deficient. Paired losses (MLH1 with PMS2, MSH2 with MSH6) reflect the heterodimers. Labels for pembrolizumab (tumour-agnostic, colorectal, endometrial), dostarlimab (endometrial and tumour-agnostic), nivolumab and ipilimumab (colorectal) and durvalumab (endometrial with chemotherapy) use 'MSI-H or dMMR' and name FDA-authorised tests; the VENTANA MMR RxDx Panel and the Agilent MMR IHC Panel pharmDx are the listed companion diagnostics. The dostarlimab label advises testing the primary tumour before temozolomide in gliomas because chemotherapy can alter dMMR results.","asOf":"2026-09-23","links":[{"label":"KEYTRUDA prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287"},{"label":"Jemperli prescribing information (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=095eab9f-545a-4f12-bfb7-19477fb901a5"}],"tags":["biomarker","mmr"],"related":["msi-high","tmb-high"],"cancers":["endometrial","endometrial-mmr-deficient","colorectal","gastric-msi-high","metastatic-cancer","tnbc","pancreatic","msi-high-pdac","gallbladder","cholangiocarcinoma","prostate"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","dostarlimab","nivolumab","ipilimumab","durvalumab","ventana-mmr-rxdx"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","mlh1-promoter-methylation","ihc","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ren-tnbc-mmr-msi-440-front-oncol-2021","paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","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","paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019","paper-wardell-biliary-drivers-germline-j-hepatol-2018","paper-guedes-msh2-loss-primary-prostate-ccr-2017","paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019"],"journals":[],"dependsOn":[],"notes":["Triple-negative breast cancer: one mismatch repair-deficient tumour (MSH2 loss) among 440 by immunohistochemistry (Ren 2021); yield is too low for routine four-protein staining outside a Lynch syndrome history.","Pancreatic ductal adenocarcinoma: four-protein immunohistochemistry is the recommended first test, with MSI PCR where the result is doubtful and next-generation sequencing where tissue is limited (Luchini 2021); loss of MLH1, MSH2, MSH6 or PMS2 was found in 7 of 833 patients, all with Lynch syndrome (Hu 2018).","Colorectal cancer: four-protein immunohistochemistry (MLH1, MSH2, MSH6, PMS2) on every colorectal cancer is the guideline route, with MSI PCR where the stain is equivocal (Sepulveda 2017). Testing everyone found 100% of Lynch syndrome carriers against 87.8% for the Bethesda guidelines, at the cost of about a third more tests (Moreira 2012). The reflex step matters: loss of MLH1 with PMS2 prompts BRAF V600E or MLH1 promoter methylation testing, because the sporadic route is CIMP-associated methylation rather than a germline variant (Herman 1998, Weisenberger 2006).","Gallbladder and biliary cancer: mismatch repair deficiency is rare (about 1 to 2.5%), and germline MLH1 or MSH2 variants were among the predisposing mutations found in 11% of biliary tract cancer patients (Wardell 2018), so a lost stain should prompt germline testing.","Prostate cancer: MSH2 protein loss in 14 of 1,176 prostatic carcinomas, 1.2%, concentrated in the highest-grade tumours at 8% of 91 with primary Gleason pattern 5 against 0.4% of 1,042 with any other score, and in 2 of 43 small cell carcinomas. Loss was homogeneous within tumours, so it is an early clonal event and the diagnostic block is an adequate place to look; sequencing confirmed loss of function in all 12 tested, with biallelic inactivation and hypermutation in 83% each and germline MSH2 mutation in 3 of 12, 25% (Guedes 2017)."],"target":"mmr","measurement":"ihc-score","scoringRule":{"text":"Loss of nuclear staining for one or more of MLH1, PMS2, MSH2 and MSH6 in tumour cells, with retained staining in internal control cells, is mismatch repair deficient.","quote":"Deficient mismatch repair (dMMR) proteins: MLH1, PMS2, MSH2 and MSH6","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools","sourceLabel":"FDA: List of FDA-Authorized Companion Diagnostic Devices"},"thresholds":[{"value":"MSI-H or dMMR, tumour-agnostic","drugId":"pembrolizumab","cancerId":"metastatic-cancer","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.","status":"current"},{"value":"MSI-H or dMMR","drugId":"pembrolizumab","cancerId":"endometrial-mmr-deficient","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","quote":"KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-authorized test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation","status":"current"},{"value":"dMMR","drugId":"dostarlimab","cancerId":"endometrial-mmr-deficient","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=095eab9f-545a-4f12-bfb7-19477fb901a5","quote":"Monotherapy Adults with dMMR recurrent or advanced EC and dMMR recurrent or advanced solid tumors 500 mg a JEMPERLI every 3 weeks for 4 cycles followed by 1,000 mg a JEMPERLI every 6 weeks for all cycles thereafter.","status":"current","note":"Dosing table wording; the indications section names dMMR recurrent or advanced endometrial cancer and dMMR solid tumours as determined by an FDA-approved test."},{"value":"MSI-H or dMMR","drugId":"nivolumab","cancerId":"colorectal","regulator":"FDA","source":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394","quote":"OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC)","status":"current"}],"tests":[],"assays":["mmr-ventana"],"companionDiagnostics":[{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["dostarlimab"],"indication":"Endometrial Carcinoma (EC) - Tissue","pma":"P200019 (04/22/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["dostarlimab"],"indication":"Solid Tumors","pma":"P210001 (08/17/2021)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["pembrolizumab"],"indication":"Solid Tumors","pma":"P210001/S001 (03/21/2022)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"Ventana MMR RxDx Panel","maker":"Ventana Medical Systems (Roche)","drugs":["durvalumab"],"indication":"Endometrial Carcinoma (EC) - Tissue","pma":"P210001/S013 (12/18/2024)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"},{"device":"MMR IHC Panel pharmDx (Dako Omnis)","maker":"Agilent Technologies","companyId":"agilent","drugs":["nivolumab","ipilimumab"],"indication":"Colorectal Cancer (CRC) - Tissue","pma":"P250004 (08/15/2025)","source":"https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools"}],"forPatient":"If your report shows loss of MLH1, PMS2, MSH2 or MSH6, your cancer is mismatch repair deficient. That opens immunotherapy (pembrolizumab, dostarlimab, nivolumab with ipilimumab depending on the cancer) and, because dMMR can be inherited as Lynch syndrome, your team should offer a germline test and advice for relatives. Loss of MLH1 alone is often caused by methylation rather than inheritance; a follow-up test tells the two apart."},"route":"/biomarkers/dmmr-ihc/","neighbours":{"biomarker":[{"id":"msi-high","kind":"biomarker","name":"MSI-high (microsatellite instability by PCR or sequencing)","route":"/biomarkers/msi-high/"},{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"},{"id":"tp53-del17p","kind":"biomarker","name":"TP53 mutation and del(17p)","route":"/biomarkers/tp53-del17p/"}],"cancer":[{"id":"cholangiocarcinoma","kind":"cancer","name":"Biliary tract cancer (cholangiocarcinoma)","route":"/cancers/cholangiocarcinoma/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"metastatic-cancer","kind":"cancer","name":"Metastatic cancer (cancer that has spread)","route":"/cancers/metastatic-cancer/"},{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","route":"/cancers/gastric-msi-high/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"endometrial-mmr-deficient","kind":"cancer","name":"Mismatch-repair-deficient endometrial cancer","route":"/cancers/endometrial-mmr-deficient/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"drug":[{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/"},{"id":"durvalumab","kind":"drug","name":"Durvalumab","route":"/drugs/durvalumab/"},{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"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":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"mlh1-promoter-methylation","kind":"term","name":"MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)","route":"/terms/mlh1-promoter-methylation/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"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-wardell-biliary-drivers-germline-j-hepatol-2018","kind":"paper","name":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","route":"/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/"},{"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-158-pembrolizumab-msi-high-noncolorectal-jco-2020","kind":"paper","name":"KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer","route":"/key-papers/paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020/"},{"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-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019","kind":"paper","name":"Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma","route":"/key-papers/paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019/"},{"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-guedes-msh2-loss-primary-prostate-ccr-2017","kind":"paper","name":"MSH2 loss in primary prostate cancer","route":"/key-papers/paper-guedes-msh2-loss-primary-prostate-ccr-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-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","kind":"paper","name":"Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade","route":"/key-papers/paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019/"}],"target":[{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"}]}}