28/05/2025
Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumour types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The prevalence of the MSI-H/dMMR phenotype is highest in endometrial and colore**al cancers, and this phenotype is associated with a distinct tumour biology, prognosis and responsiveness to various anticancer treatments. In a minority of patients, MSI-H/dMMR cancers result from an inherited pathogenic variant in the context of Lynch syndrome, which has important implications for familial genetic screening. Whether these hereditary cancers have a different biology and clinical behaviour to their sporadic counterparts remains uncertain. Interest in this tumour molecular subtype has increased following the discovery of the high sensitivity of metastatic MSI-H/dMMR cancers to immune-checkpoint inhibitors (ICIs) in a histology-agnostic manner, which reflects the genomic hypermutation resulting from dMMR that renders these tumours highly immunogenic and immune infiltrated. This vulnerability is now also being exploited in early stage disease settings. Despite this common biological foundation, different MSI-H/dMMR cancers have histotype-specific features that correspond to their particular cell or tissue of origin, which might be associated with differences in prognosis and sensitivity to ICIs. In this Review, we provide an overview of the epidemiology, biology, pathogenesis, clinical diagnosis and treatment of MSI-H/dMMR tumours as a histology-agnostic cancer phenomenon. We also highlight peculiarities associated with specific pathogenetic alterations and histologies of MSI-H/dMMR tumours.
