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@ARTICLE{Helderman:300094,
      author       = {N. C. Helderman and F. Strobel$^*$ and L. Bohaumilitzky$^*$
                      and D. Terlouw and A.-S. van der Werf-'t Lam and T. van
                      Wezel and H. Morreau and M. von Knebel Doeberitz$^*$ and M.
                      Nielsen and M. Kloor$^*$ and A. Ahadova$^*$},
      title        = {{L}ower degree of microsatellite instability in colorectal
                      carcinomas from {MSH}6-associated {L}ynch syndrome
                      patients.},
      journal      = {Modern pathology},
      volume       = {38},
      number       = {7},
      issn         = {0893-3952},
      address      = {London},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2025-00594},
      pages        = {100757},
      year         = {2025},
      note         = {#LA:D470# / Volume 38, Issue 7, July 2025, 100757},
      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 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.},
      keywords     = {Lynch syndrome (Other) / coding microsatellites (Other) /
                      colorectal cancer (Other) / frameshift peptides (Other) /
                      microsatellite instability (Other) / mismatch repair
                      (Other)},
      cin          = {D470},
      ddc          = {610},
      cid          = {I:(DE-He78)D470-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40118460},
      doi          = {10.1016/j.modpat.2025.100757},
      url          = {https://inrepo02.dkfz.de/record/300094},
}