# Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)

Source: https://onco.cc/terms/msi/  
OnCo record `msi` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Term
- Last checked: 2026-09-04
- Also known as: MSI-high; microsatellite instability-high; mismatch repair-deficient; mismatch repair deficient; MMR-deficient; MMR deficiency; MMRd; MMR immunohistochemistry; mismatch repair immunohistochemistry; MMR IHC; mismatch repair proteins; MLH1, MSH2, MSH6 and PMS2; MSI by PCR; microsatellite instability testing; MSI testing

## Notes

- Colorectal cancer: 10 to 15% of resected disease but only about 5% of first-line metastatic disease (153 of 3,063; Venderbosch 2014) and 3.5% in one advanced cohort (Koopman 2009), because unstable tumours metastasise less readily. The mechanism that makes them cancers is slippage in coding microsatellites: TGFBR2 was the first such target identified (Markowitz 1995), and ACVR2A, RNF43 and B2M follow. The mechanism that makes them treatable is mutation load, a mean of 1,782 somatic mutations against 73 in proficient tumours (Le 2015).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability
- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability

## Connected records

- cancers: [Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable)](https://onco.cc/cancers/advanced-adrenocortical-carcinoma/), [Advanced and metastatic small bowel adenocarcinoma](https://onco.cc/cancers/advanced-small-bowel-adenocarcinoma/), [Advanced or recurrent endometrial cancer](https://onco.cc/cancers/advanced-recurrent-endometrial-cancer/), [Appendiceal adenocarcinoma (mucinous and non-mucinous, including signet ring cell)](https://onco.cc/cancers/appendiceal-adenocarcinoma/), [BRAF V600E-mutant colorectal cancer](https://onco.cc/cancers/braf-v600e-colorectal/), [Cancer of unknown primary (CUP)](https://onco.cc/cancers/cancer-of-unknown-primary/), [Cancer of unknown primary, unfavourable (adenocarcinoma and poorly differentiated carcinoma)](https://onco.cc/cancers/cup-unfavourable/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Early-onset colorectal cancer (under 50)](https://onco.cc/cancers/early-onset-colorectal/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Extrahepatic cholangiocarcinoma (perihilar and distal)](https://onco.cc/cancers/extrahepatic-cholangiocarcinoma/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [Localised small bowel adenocarcinoma (stage I to III, resected)](https://onco.cc/cancers/localised-small-bowel-adenocarcinoma/), [Lynch syndrome-associated colorectal cancer](https://onco.cc/cancers/lynch-associated-colorectal-cancer/), [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Microsatellite-unstable (MSI-high) gastric cancer](https://onco.cc/cancers/gastric-msi-high/), [Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma](https://onco.cc/cancers/msi-high-pdac/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/), [Mismatch-repair-deficient endometrial cancer](https://onco.cc/cancers/endometrial-mmr-deficient/), [Pancreatic acinar cell carcinoma](https://onco.cc/cancers/pancreatic-acinar-cell-carcinoma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Rectal cancer](https://onco.cc/cancers/rectal-cancer/), [Small intestine cancer (small bowel adenocarcinoma)](https://onco.cc/cancers/small-bowel/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- drugs: [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Envafolimab](https://onco.cc/drugs/envafolimab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [TruSight Oncology Comprehensive](https://onco.cc/drugs/trusight-oncology-comprehensive/), [VENTANA MMR RxDx Panel](https://onco.cc/drugs/ventana-mmr-rxdx/)
- key papers: [Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study (QUASAR)](https://onco.cc/key-papers/paper-quasar-adjuvant-chemotherapy-vs-observation-lancet-2007/), [Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial](https://onco.cc/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/), [CAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years](https://onco.cc/key-papers/paper-capp2-aspirin-lynch-lancet-2020/), [Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency](https://onco.cc/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/), [CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma](https://onco.cc/key-papers/paper-checkmate-649-lancet-2021/), [Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer](https://onco.cc/key-papers/paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014/), [Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications](https://onco.cc/key-papers/paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021/), [Comprehensive molecular characterization of human colon and rectal cancer](https://onco.cc/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/), [CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer](https://onco.cc/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/), [Deficient mismatch repair system in patients with sporadic advanced colorectal cancer](https://onco.cc/key-papers/paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009/), [Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features](https://onco.cc/key-papers/paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014/), [First trial of a vaccine against the shared neoantigens of mismatch-repair-deficient cancers](https://onco.cc/key-papers/paper-lynch-frameshift-vaccine-ccr-2020/), [Genetic instability in colorectal cancers](https://onco.cc/key-papers/paper-lengauer-genetic-instability-colorectal-nature-1997/), [Genetic mechanisms of immune evasion in colorectal cancer](https://onco.cc/key-papers/paper-grasso-immune-evasion-colorectal-cancer-discov-2018/), [Genomic correlates of immune-cell infiltrates in colorectal carcinoma](https://onco.cc/key-papers/paper-giannakis-genomic-correlates-immune-colorectal-cell-rep-2016/), [Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population](https://onco.cc/key-papers/paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025/), [Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations](https://onco.cc/key-papers/paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018/), [Identification of Lynch syndrome among patients with colorectal cancer](https://onco.cc/key-papers/paper-moreira-lynch-syndrome-identification-jama-2012/), [Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability](https://onco.cc/key-papers/paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995/), [Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma](https://onco.cc/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/), [Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability](https://onco.cc/key-papers/paper-mlecnik-immunoscore-msi-colorectal-immunity-2016/), [International validation of the consensus Immunoscore for the classification of colon cancer](https://onco.cc/key-papers/paper-pages-immunoscore-international-validation-lancet-2018/), [KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer](https://onco.cc/key-papers/paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020/), [KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer](https://onco.cc/key-papers/paper-keynote-177-nejm-2020/), [KEYNOTE-199: pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-antonarakis-keynote-199-pembrolizumab-jco-2020/), [Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ](https://onco.cc/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/), [Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up](https://onco.cc/key-papers/paper-esmo-localised-colon-cancer-guideline-ann-oncol-2020/), [Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up](https://onco.cc/key-papers/paper-esmo-metastatic-colorectal-cancer-guideline-ann-oncol-2023/), [Microsatellite instability in Japanese female patients with triple-negative breast cancer](https://onco.cc/key-papers/paper-kurata-japanese-tnbc-msi-breast-cancer-2020/), [Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients](https://onco.cc/key-papers/paper-ren-tnbc-mmr-msi-440-front-oncol-2021/), [Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma](https://onco.cc/key-papers/paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019/), [Mismatch repair status and BRAF mutation status in metastatic colorectal cancer: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies](https://onco.cc/key-papers/paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014/), [Molecular biomarkers for the evaluation of colorectal cancer: guideline from ASCP, CAP, AMP and ASCO](https://onco.cc/key-papers/paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017/), [Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/), [Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets](https://onco.cc/key-papers/paper-weinberg-biliary-profiling-jgo-2019/), [MSH2 loss in primary prostate cancer](https://onco.cc/key-papers/paper-guedes-msh2-loss-primary-prostate-ccr-2017/), [NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients](https://onco.cc/key-papers/paper-niche-2-nejm-2024/), [Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142)](https://onco.cc/key-papers/paper-overman-checkmate-142-nivolumab-dmmr-colorectal-lancet-oncol-2017/), [Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW)](https://onco.cc/key-papers/paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024/), [Nonoperative management of mismatch repair-deficient tumors](https://onco.cc/key-papers/paper-cercek-nonoperative-management-mismatch-repair-deficient-tumours-nejm-2025/), [Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial (FOxTROT)](https://onco.cc/key-papers/paper-foxtrot-preoperative-chemotherapy-colon-jco-2023/), [Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines](https://onco.cc/key-papers/paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019/), [Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade](https://onco.cc/key-papers/paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019/), [Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours](https://onco.cc/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/), [Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers](https://onco.cc/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/), [RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer](https://onco.cc/key-papers/paper-ruby-nejm-2023/), [Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia](https://onco.cc/key-papers/paper-crockett-nagtegaal-serrated-neoplasia-gastroenterology-2019/), [The consensus molecular subtypes of colorectal cancer](https://onco.cc/key-papers/paper-cms-guinney-nat-med-2015/), [The serrated pathway to colorectal carcinoma: current concepts and challenges](https://onco.cc/key-papers/paper-bettington-serrated-pathway-colorectal-histopathology-2013/)
- trials: [A Study of Botensilimab and Balstilimab for the Treatment of Colorectal Cancer](https://onco.cc/trials/nct05608044/), [ATOMIC (Alliance A021502)](https://onco.cc/trials/atomic/), [AZUR-1](https://onco.cc/trials/azur-1/), [CAVE mCRC](https://onco.cc/trials/cave/), [CheckMate 142](https://onco.cc/trials/checkmate-142/), [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [DUO-E / GOG-3041 / ENGOT-EN10](https://onco.cc/trials/duo-e/), [IMblaze370](https://onco.cc/trials/imblaze370/), [KEYNOTE-158](https://onco.cc/trials/keynote-158/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [NICHE-2](https://onco.cc/trials/niche-2/), [NRG-GY018 / KEYNOTE-868](https://onco.cc/trials/nrg-gy018-keynote-868/), [PETACC-3](https://onco.cc/trials/petacc-3/), [RUBY / ENGOT-EN6 / GOG-3031](https://onco.cc/trials/ruby/)
- terms: [Biomarker](https://onco.cc/terms/biomarker/), [Colorectal cancer: the failed and stopped programmes, and why](https://onco.cc/terms/colorectal-failed-programmes/), [CpG island methylator phenotype (CIMP)](https://onco.cc/terms/cimp/), [Enabling characteristic: genome instability and mutation](https://onco.cc/terms/genome-instability-mutation/), [Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP)](https://onco.cc/terms/endometrial-molecular-classes/), [Genome-wide loss of heterozygosity (gLOH)](https://onco.cc/terms/genome-wide-loss-of-heterozygosity/), [HER2 and genomic testing for biliary cancer on the NHS](https://onco.cc/terms/genomic-testing-biliary-uk/), [Immuno-oncology (IO) and checkpoint blockade](https://onco.cc/terms/immuno-oncology/), [Immunoscore](https://onco.cc/terms/immunoscore/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Lynch syndrome testing after bowel cancer, and what it means for the family](https://onco.cc/terms/lynch-syndrome-testing-uk/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/), [MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)](https://onco.cc/terms/mlh1-promoter-methylation/), [No specific molecular profile (NSMP) endometrial cancer](https://onco.cc/terms/nsmp/), [POLE ultramutation (POLEmut)](https://onco.cc/terms/pole-ultramutation/), [Serrated pathway](https://onco.cc/terms/serrated-pathway/)
- pairings: [Chemotherapy + PD-1/PD-L1 blockade, first-line advanced endometrial cancer](https://onco.cc/pairings/chemo-io-first-line-endometrial/), [Neoadjuvant checkpoint inhibitor → surgery (or no surgery) in dMMR colorectal cancer](https://onco.cc/pairings/neoadjuvant-io-dmmr/)
- ideas: [A frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval](https://onco.cc/ideas/idea-moon-lynch-vaccine-phase3/), [A funded programme of organ-preservation trials to avoid radical surgery](https://onco.cc/ideas/idea-fund-organ-preservation-programme/), [A randomised trial of a shared-antigen vaccine to prevent Lynch syndrome cancers](https://onco.cc/ideas/idea-prev-lynch-frameshift-vaccine-rct/), [A standard for tumour-agnostic approvals: minimum histologies and hierarchical modelling](https://onco.cc/ideas/idea-tr1-tumour-agnostic-approval-standard/), [Automatic germline testing for every cancer type where it changes care](https://onco.cc/ideas/idea-prev-reflex-germline-testing/), [Get every Lynch syndrome carrier onto the right dose of aspirin](https://onco.cc/ideas/idea-prev-lynch-aspirin-implementation/), [Making microsatellite-stable colorectal cancer immunotherapy-responsive](https://onco.cc/ideas/idea-immunotherapy-mss-crc/), [Molecular-class-directed adjuvant therapy in endometrial cancer](https://onco.cc/ideas/idea-molecular-class-adjuvant-endometrial/), [Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed](https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/), [Standing reflex biomarker panels per tumour type, run without an oncologist's order](https://onco.cc/ideas/idea-acc-reflex-biomarker-panels-by-tumour/), [The pathology lab triggers a trial referral the day a rare cancer is diagnosed](https://onco.cc/ideas/idea-tr1-pathology-triggered-referral/), [Unmask hidden antigens with a short epigenetic course before immunotherapy](https://onco.cc/ideas/idea-bio2-epigenetic-priming-cold-tumours/), [WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers](https://onco.cc/ideas/idea-bio1-wrn-msi-programme/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [MSI and mismatch-repair testing](https://onco.cc/technologies/msi-mmr-testing/), [Tumour mutational burden testing](https://onco.cc/technologies/tmb-testing/)
- companies: [Nouscom](https://onco.cc/companies/nouscom/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- people: [Aurélien Marabelle](https://onco.cc/people/aurelien-marabelle/), [Myriam Chalabi](https://onco.cc/people/myriam-chalabi/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [WRN helicase (MSI-high cancers)](https://onco.cc/targets/wrn/)
- collections: [Colorectal Cancer Alliance](https://onco.cc/collections/colorectal-cancer-alliance/)
- pathways: [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)
- biomarkers: [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/), [MSI-high (microsatellite instability by PCR or sequencing)](https://onco.cc/biomarkers/msi-high/)

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