TY  - JOUR
AU  - Helderman, Noah C
AU  - Strobel, Fabian
AU  - Bohaumilitzky, Lena
AU  - Terlouw, Diantha
AU  - van der Werf-'t Lam, Anne-Sophie
AU  - van Wezel, Tom
AU  - Morreau, Hans
AU  - von Knebel Doeberitz, Magnus
AU  - Nielsen, Maartje
AU  - Kloor, Matthias
AU  - Ahadova, Aysel
TI  - Lower degree of microsatellite instability in colorectal carcinomas from MSH6-associated Lynch syndrome patients.
JO  - Modern pathology
VL  - 38
IS  - 7
SN  - 0893-3952
CY  - London
PB  - Nature Publishing Group
M1  - DKFZ-2025-00594
SP  - 100757
PY  - 2025
N1  - #LA:D470# / Volume 38, Issue 7, July 2025, 100757
AB  - 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 to 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 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. 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 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 to 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.
KW  - Lynch syndrome (Other)
KW  - coding microsatellites (Other)
KW  - colorectal cancer (Other)
KW  - frameshift peptides (Other)
KW  - microsatellite instability (Other)
KW  - mismatch repair (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40118460
DO  - DOI:10.1016/j.modpat.2025.100757
UR  - https://inrepo02.dkfz.de/record/300094
ER  -