Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)
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.
Overview
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
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.
External identifiers
What a pathology or genomic report can say about this target, each with the thresholds approvals use.
Biology
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.
- Colorectal cancer (about 15 percent, most sporadic through MLH1 methylation)
- Endometrial cancer (about 25 to 30 percent)
- Gastric, small bowel, urothelial and other Lynch-spectrum tumours
Notes
top- Per-gene identifiers from HGNC: MLH1 HGNC:7127, ENSG00000076242, UniProt P40692; MSH2 HGNC:7325, ENSG00000095002, UniProt P43246; MSH6 HGNC:7329, ENSG00000116062, UniProt P52701; PMS2 HGNC:9122, ENSG00000122512, UniProt P54278.
Latest papers
topQuery 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.
Similar pages
not linked directly; found by shared links- TechnologyMSI and mismatch-repair testing
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss), Dostarlimab, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
- TargetPTEN
Shares Endometrial cancer and the tag biomarker-parent.
- TreatmentVENTANA MMR RxDx Panel
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), dMMR (mismatch repair deficiency by IHC), Dostarlimab, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
- PairingChemotherapy + PD-1/PD-L1 blockade, first-line advanced endometrial cancer
Shares Mismatch-repair-deficient endometrial cancer, Dostarlimab, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Endometrial cancer.
- TermImmuno-oncology (IO) and checkpoint blockade
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Nivolumab, Pembrolizumab.
- TrialEIK1005-002: A Clinical Research Study Evaluating EIK1005, a Werner Helicase Inhibitor, as Monotherapy and in Combination With Pembrolizumab in Partic
Shares Mismatch-repair-deficient endometrial cancer, Endometrial cancer, Pembrolizumab, Colorectal cancer.
- Key paperLe 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval
Shares Microsatellite-unstable (MSI-high) gastric cancer, Dostarlimab, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Nivolumab.
- TrialA Study of Dostarlimab in Combination With Carboplatin-paclitaxel in Chinese Participants With Primary Advanced or Recurrent Endometrial Cancer (EC)
Shares Mismatch-repair-deficient endometrial cancer, Dostarlimab, Endometrial cancer.