Fig. 1: Mechanisms of MMR loss and the corresponding genomic and immunological sequelae.

DNA mismatch repair deficiency (MMRd) arises from biallelic inactivation of one of the four mismatch repair (MMR) genes. Loss of MMR function can occur through three different mechanisms. Sporadic MMRd describes the somatic inactivation of both alleles of an MMR gene. Lynch syndrome is a hereditary cancer predisposition syndrome characterized by germline heterozygous inactivation of one allele of an MMR gene; MMRd develops following somatic loss of the remaining wild-type allele. Finally, constitutional MMRd arises from germline biallelic inactivation of an MMR gene. MMRd can be diagnosed using immunohistochemistry (IHC). MSH2 and MLH1 are obligatory binding partners that stabilize their respective heterodimers. MSH2 loss therefore manifests as loss of MSH2 and MSH6 on IHC, and MLH1 loss manifests as loss of both MLH1 and PMS2. By contrast, MSH6 and PMS2 mutations lead to isolated losses of the respective proteins. Although the timing of biallelic MMR inactivation remains unclear in sporadic MMRd cancers, data from patients with Lynch syndrome indicate that small adenomas can be MMR proficient. Larger adenomas are more likely to be MMRd but can still be microsatellite stable. More advanced adenomas and colorectal cancer can then become microsatellite instability high (MSI-H). Once MMRd, cells can accumulate a large number of mutations over the course of time and many divisions. These tend to be single-base substitutions and insertions and/or deletions (indels), which can occur throughout the genome although microsatellites are particularly susceptible owing to their propensity for strand slippage during DNA replication. Indels that cause frameshift mutations within coding-region microsatellites are more likely to have functionally important consequences (such as inactivation of tumour-suppressor genes). Moreover, frameshift mutations can give rise to foreign-appearing peptides that are likely to contain immunogenic neoepitopes, which are thought to elicit the robust antitumour immune responses seen in MMRd cancers. CMMRD, constitutional mismatch repair deficiency; TMB-H, high tumour mutational burden; TILs, tumour-infiltrating lymphocytes.