Lower Degree of Microsatellite Instability in Colorectal Carcinomas From MSH6-Associated Lynch Syndrome Patients

Abstract

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 (path_MMR). Recently, we demonstrated that colorectal carcinomas in path_MSH6 carriers exhibit fewer insertion/deletion mutations compared with cumulative colorectal cancers (CRCs) from other MMR groups, raising the question of whether MSH6-mutated CRCs might display a relatively lower degree of microsatellite instability (MSI). Mutations at 20 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. MSH6-mutated CRCs exhibited lower mutation frequencies and mutant allele ratios across most cMS. Variation in cMS mutation patterns was observed both between different tumor regions and between tumor tissue and adjacent adenomatous tissue. The cMS mutations in MSH6-mutated CRCs demonstrated inverse correlations with the predicted immunogenicity of the resulting frameshift peptides, which may suggest a negative selection of cell clones bearing highly immunogenic frameshift peptides. Overall, MSH6-mutated CRCs display a relatively lower degree of MSI and represent a biologically distinct subgroup of LS-associated CRCs. This lower MSI level may implicate an altered immune response compared with other MSI CRCs, which could have theoretical 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.