Lower degree of microsatellite instability in colorectal carcinomas fromMSH6-associated Lynch syndrome patients

Abstract Background Numerous observational and molecular studies focusing on Lynch syndrome (LS) have revealed significant variation in the phenotype and molecular characteristics among carriers of pathogenic variants in mismatch repair genes (pathMMR). Recently, we demonstrated that colorectal carcinomas in pathMSH6 carriers exhibit fewer insertion/deletion mutations compared to CRCs from other MMR groups, raising the question of whether MSH6 -mutated CRCs might display a lower degree of microsatellite instability (MSI). Methods Mutations at twenty coding microsatellites (cMS) were analyzed in 39 MSH6 -, 18 MLH1 -, 16 MSH2 - and 22 PMS2 -mutated CRCs and 35 sporadic MSI CRCs, and mutation frequencies and mutant allele ratios were compared among the different MMR-deficient groups. Considering factors such as HLA-A *02: 01 type, B2M status, and the anticipated immunogenicity of frameshift peptides derived from cMS mutations, the identified cMS mutation profiles of MSH6 -mutated CRCs were further investigated to assess their potential impact on immunotherapeutic strategies. Results MSH6 -mutated CRCs exhibited lower mutation frequencies and mutant allele ratios across most cMS. The cMS mutations in MSH6 -mutated CRCs demonstrated inverse correlations with the predicted immunogenicity of the resulting frameshift peptides, which may suggest negative selection of cell clones bearing highly immunogenic frameshift peptides. Conclusions MSH6 -mutated CRCs display a lower degree of MSI, which may be connected to lower penetrance and later onset of the disease in pathMSH6 carriers. Moreover, this lower MSI level may implicate an altered immune response compared to other MSI CRCs, which could have implications for the success of immunotherapy in MSH6 -mutated CRCs. Future studies should carefully evaluate this possibility. If confirmed, these results would reinforce the notion of classifying LS as distinct syndromes associated with specific MMR genes.