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Acquisition Process and Clinical Relevance of dMMR-Associated Mutational Signatures in Hepatocellular Carcinoma

  • 0Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Liver International : Official Journal of the International Association for the Study of the Liver +

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June 25, 2025

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June 25, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Mismatch repair deficiency (dMMR)-associated mutational signatures are found in hepatocellular carcinoma (HCC) and can predict immunotherapy response. These signatures indicate treatment efficacy even without reduced mismatch repair protein levels.

Area Of Science

  • Genomics
  • Cancer Biology
  • Oncology

Background

  • Hepatocellular carcinoma (HCC) treatment requires predicting efficacy for personalized strategies.
  • Mutational signatures offer insights into cancer development and serve as potential biomarkers.
  • Mismatch repair deficiency (dMMR)-associated signatures require further investigation in HCC.

Purpose Of The Study

  • To investigate the development and clinical significance of dMMR-associated mutational signatures in HCC.
  • To correlate these signatures with tumor progression and response to immunotherapy.

Main Methods

  • Whole-genome sequencing of 529 HCC and non-cancerous samples to analyze mutational signatures.
  • Multi-omics analysis of 239 HCC samples for molecular correlations.
  • Whole-exome sequencing of 75 HCC samples to assess immunotherapy response.

Main Results

  • dMMR-associated signatures were prevalent in HCC subclonal mutations but absent in normal liver tissue.
  • These signatures correlated with advanced tumor stage, larger size, cell cycle gene upregulation, and lower IL6 expression.
  • A higher proportion of dMMR signatures predicted better response and longer progression-free survival to atezolizumab plus bevacizumab.

Conclusions

  • dMMR-associated signatures can arise in HCC without reduced mismatch repair protein expression, particularly in later stages.
  • These signatures represent a novel biomarker for predicting immunotherapy efficacy in HCC.

Keywords: