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

  • 0Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc +

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March 21, 2025

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March 21, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Lynch syndrome (LS) patients with MSH6 gene mutations have fewer microsatellite instability (MSI) mutations in colorectal cancer (CRC). This distinct molecular profile may impact immune response and immunotherapy effectiveness in MSH6-mutated CRCs.

Area Of Science

  • Oncology
  • Genetics
  • Cancer Research

Background

  • Lynch syndrome (LS) is linked to inherited mismatch repair (MMR) gene mutations, causing colorectal cancer (CRC).
  • Phenotypic and molecular variations exist among LS patients with different MMR gene mutations.
  • Previous research suggested MSH6-mutated CRCs might have lower microsatellite instability (MSI).

Purpose Of The Study

  • To investigate and compare microsatellite instability (MSI) levels in colorectal cancers (CRCs) associated with different mismatch repair (MMR) gene mutations, particularly MSH6.
  • To analyze coding microsatellite (cMS) mutation profiles in MSH6-mutated CRCs and assess their potential impact on immunogenicity and immunotherapy.

Main Methods

  • Analysis of mutations in 20 coding microsatellites (cMS) across 39 MSH6-, 18 MLH1-, 16 MSH2-, and 22 PMS2-mutated CRCs, plus 35 sporadic MSI CRCs.
  • Comparison of mutation frequencies and mutant allele ratios among different MMR-deficient groups.
  • Investigation of cMS mutation profiles in MSH6-mutated CRCs, considering HLA-A*02:01, B2M status, and predicted immunogenicity of frameshift peptides.

Main Results

  • MSH6-mutated CRCs exhibited significantly lower mutation frequencies and mutant allele ratios across most cMS compared to other MMR groups.
  • MSH6-mutated CRCs showed an inverse correlation between cMS mutations and the predicted immunogenicity of resulting frameshift peptides.
  • Tumor region and adjacent adenomatous tissue showed variation in cMS mutation patterns.

Conclusions

  • MSH6-mutated CRCs represent a distinct molecular subgroup of LS-associated CRCs with a relatively lower degree of MSI.
  • The altered MSI profile in MSH6-mutated CRCs may suggest a different immune response, potentially affecting immunotherapy outcomes.
  • These findings support classifying LS as distinct syndromes based on specific MMR gene mutations.

Keywords:

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