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The four mismatch repair proteins proofread newly copied DNA; when a tumour loses one of them its DNA fills with small errors, and that state (dMMR or MSI-high) is what lets immunotherapy work across many cancers.
MLH1, MSH2, MSH6 and PMS2 form the MutS and MutL complexes that recognise and excise base mismatches and slipped repeats after replication. Loss of any one, by germline mutation (Lynch syndrome), somatic mutation or MLH1 promoter methylation, produces mismatch repair deficiency, read directly by immunohistochemistry for the four proteins or indirectly as microsatellite instability by PCR or sequencing. The two readouts under this record carry the label thresholds for pembrolizumab, nivolumab, ipilimumab, dostarlimab and durvalumab and the companion diagnostics that report them.
In plain words · The four mismatch repair proteins proofread newly copied DNA; when a tumour loses one of them its DNA fills with small errors, and that state (dMMR or MSI-high) is what lets immunotherapy work across many cancers.
The four mismatch repair proteins proofread newly copied DNA; when a tumour loses one of them its DNA fills with small errors, and that state (dMMR or MSI-high) is what lets immunotherapy work across many cancers.
Deficient repair raises the mutation rate a hundredfold and produces frameshift neoantigens in repeat-containing genes, which is the mechanistic basis for checkpoint inhibitor sensitivity.
No product in this corpus aims at Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) yet. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Tumour-associated overexpression or amplification: 1 of 2 label readouts filed under it score protein level or gene copies (dMMR (mismatch repair deficiency by IHC)), so the medicines rely on the tumour carrying more of it than normal tissue. HPA MLH1: RNA low tissue specificity; high antibody staining in 32 normal tissues; highest cancer staining cervical cancer (7 of 11 high). HPA MSH2: RNA low tissue specificity; high antibody staining in 2 normal tissues; highest cancer staining glioma (4 of 12 high). HPA MSH6: RNA low tissue specificity; high antibody staining in 35 normal tissues; highest cancer staining breast cancer (11 of 11 high). HPA PMS2: RNA low tissue specificity; high antibody staining in 3 normal tissues; highest cancer staining glioma (3 of 12 high). Distribution: 4 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Biliary tract cancer (all types), Colorectal cancer, Endometrial cancer, Gastric & gastro-oesophageal junction cancer); approvals of single-target medicines aimed at it also list Pancreatic ductal adenocarcinoma, Breast cancer (all types), Lung cancer (all types), Skin cancer (all types) and more, not counted; Open Targets associates it with 27 specific cancer types at or above 0.5 (Lynch syndrome, colorectal cancer, mismatch repair cancer syndrome 1, Muir-Torre syndrome, colon carcinoma, mismatch repair cancer syndrome and more). Tissue-agnostic: dMMR (mismatch repair deficiency by IHC) threshold "MSI-H or dMMR, tumour-agnostic" for Pembrolizumab is tissue-agnostic; MSI-high (microsatellite instability by PCR or sequencing) threshold "MSI-H or dMMR, tumour-agnostic" for Pembrolizumab is tissue-agnostic; Pembrolizumab US 2017: "MSI-H/dMMR solid tumours (tumour-agnostic)". (Rule 3 of scripts/fetch-target-specificity.ts.)
Sources: dMMR (mismatch repair deficiency by IHC) label threshold; Human Protein Atlas MLH1 tissue; Human Protein Atlas MLH1 pathology; Human Protein Atlas MSH2 tissue; Human Protein Atlas MSH2 pathology; Human Protein Atlas MSH6 tissue; Human Protein Atlas MSH6 pathology; Human Protein Atlas PMS2 tissue; Human Protein Atlas PMS2 pathology; Open Targets ENSG00000076242 associations; Open Targets ENSG00000095002 associations
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Deficient repair raises the mutation rate a hundredfold and produces frameshift neoantigens in repeat-containing genes, which is the mechanistic basis for checkpoint inhibitor sensitivity.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adipose tissue, Bone marrow, Breast, Caudate, Liver, Lymph node, Ovary, Parathyroid gland.
Medium only: carcinoid, liver cancer.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adipose tissue, Adrenal gland, Appendix, Bone marrow, Breast, Bronchus, Caudate, Cerebellum.
RNA cancer enhanced: Testicular Germ Cell Tumor 90 pTPM.
Medium only: breast cancer, cervical cancer, endometrial cancer, head and neck cancer.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Cerebellum, Heart muscle, Hippocampus, Liver, Parathyroid gland, Skeletal muscle, Small intestine, Smooth muscle.
RNA cancer enhanced: Testicular Germ Cell Tumor 118 pTPM.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Adrenal gland, Appendix, Breast, Bronchus, Caudate, Cervix, Colon, Duodenum.
Medium only: carcinoid, cervical cancer, colorectal cancer, endometrial cancer.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Colorectal cancer | 5-15% | Microsatellite instability or mismatch repair deficiency | Stage matters more than anything else. In unselected surgical series: 38 of 276, 13.8%, MSI-high in the TCGA cohort with a further 44 MSI-low (Cancer Genome Atlas Network 2012); 91 of 529, 17.2%, in the 619-exome prospective cohort (Giannakis 2016); 770 of 7,217, 10.7%, in crc_msk_2026, which splits into 710 of 5,138 primaries (13.8%) and 59 of 2,045 metastases (2.9%); 125 of 1,513, 8.3%, in crc_eo_2020; 76 of 1,015, 7.5%, in crc_sysucc_2022 (cBioPortal). In first-line metastatic trial populations it collapses: 153 of 3,063, 5.0%, pooled across CAIRO, CAIRO2, COIN and FOCUS (Venderbosch 2014) and 18 of 515, 3.5%, in a phase 3 advanced cohort, 13 of them from MLH1 promoter hypermethylation (Koopman 2009). | doi.org |
| Gallbladder cancer | 0.6-2.5% | Microsatellite instability (MSI-high) | 6 of 244 samples, 2.5%, called unstable by MSIsensor in cBioPortal gbc_mskcc_2022; 0.6% (2 of 170 tested) in Indian patients (Suryavanshi 2025); 1.3% (4 of 308) in Western cholangiocarcinoma by mononucleotide markers (Goeppert 2019); gallbladder and intrahepatic tumours carried more MSI-high, PD-L1 and TMB-high than extrahepatic (Weinberg 2019). | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 0.5-2% | Mismatch repair deficiency or microsatellite instability | 7 of 833, 0.8%, all with Lynch syndrome, 4 of 7 benefiting from checkpoint blockade (Hu 2018, Clin Cancer Res); MSI-high and/or TMB-high in 0.5% of 2,563 assessed (Singhi 2019); 1 to 2% across 34 studies and 8,323 patients, associated with medullary and colloid histology and KRAS/TP53 wild-type background (Luchini 2021); 4.7% of KRAS wild-type against 0.7% of KRAS-mutant tumours (Philip 2022); cBioPortal: MSI_TYPE unstable in 6 of 1,119 reported samples and MSIsensor score 10 or more in 10 of 2,314 in pdac_msk_2024; 2 of 323 reported in pancreas_msk_2024; no TCGA sample reached MANTIS 0.4. Germline MLH1 0.13% of 3,030, odds ratio 6.66 (Hu 2018, JAMA). | doi.org |
| Triple-negative breast cancer | 0-2% | Microsatellite instability or mismatch repair deficiency | No MSI-high tumour among 195 by PCR and one mismatch-repair-deficient tumour (lost MSH2) among 440 by IHC in Chinese TNBC (Ren 2021); 2 of 228 Japanese TNBCs MSI-high, 0.9% (Kurata 2020); about 4.7% of HRDetect-low tumours, roughly 1.7% of all 237 whole genomes, mismatch-repair deficient (Staaf 2019); cBioPortal: MSIsensor score 10 or more in 3 of 122 triple-negative exomes in brca_tcga_pan_can_atlas_2018, an algorithmic call not confirmed by PCR. | doi.org |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
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.
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.
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.
This is the fusion and immune-marker table for the wild-type minority, the group in which RNA sequencing pays for itself.
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.
Query for this target: (TITLE:"Mismatch repair proteins" OR ABSTRACT:"Mismatch repair proteins" OR TITLE:"MLH1, MSH2, MSH6, PMS2" OR ABSTRACT:"MLH1, MSH2, MSH6, PMS2" OR TITLE:"MLH1" OR ABSTRACT:"MLH1" OR TITLE:"MSH2" OR ABSTRACT:"MSH2" OR TITLE:"MSH6" OR ABSTRACT:"MSH6" OR TITLE:"PMS2" OR ABSTRACT:"PMS2") 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 Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), not a curated reading list.
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 Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability, Deficient mismatch repair system in patients with sporadic advanced colorectal cancer, Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features, Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications.
Shares Endometrial cancer, Triple-negative breast cancer (TNBC), Colorectal cancer and the tag biomarker-parent.
Shares Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, Molecular biomarkers for the evaluation of colorectal cancer: guideline from ASCP, CAP, AMP and ASCO, Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), Identification of Lynch syndrome among patients with colorectal cancer.
Shares Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer, 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.
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 Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer, Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population, Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers, Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma.
Shares Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1, Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer, MSH2 loss in primary prostate cancer, Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations.