MSI and mismatch-repair testing
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.
Overview
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.
How it works
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.
- Cheap immunohistochemistry available everywhere
- Identifies the most immunotherapy-responsive tumours
- Doubles as Lynch syndrome screening
- 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
Latest papers
topQuery for this technology: (TITLE:"MSI and mismatch-repair testing" OR ABSTRACT:"MSI and mismatch-repair testing") 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 MSI and mismatch-repair testing, not a curated reading list.
Pages like this
not linked directly; found by shared links- TechnologyTumour mutational burden testing
Shares FoundationOne CDx / Liquid CDx, Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Companion diagnostics.
- PathwayMismatch repair & microsatellite instability
Shares Lynch syndrome, Dostarlimab, Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
- TermImmuno-oncology (IO) and checkpoint blockade
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Pembrolizumab.
- Key paperCAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years
Shares Lynch syndrome, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Germline (hereditary) testing, Endometrial cancer.
- TargetWRN helicase (MSI-high cancers)
Shares Lynch syndrome, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Endometrial cancer, Gastric & gastro-oesophageal junction cancer.
- PairingChemotherapy + PD-1/PD-L1 blockade, first-line advanced endometrial cancer
Shares Dostarlimab, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Endometrial cancer, Pembrolizumab.
- PersonAurélien Marabelle
Shares Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Pembrolizumab.
- IdeaA funded programme of organ-preservation trials to avoid radical surgery
Shares Dostarlimab, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Pembrolizumab, Colorectal cancer.