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

Multiple systemic therapies have received approval for hepatocellular carcinoma (HCC), necessitating the prediction of treatment efficacy to promote personalised treatment strategies. Mutational signatures reflect the mutational processes in human cancers and have emerged as promising biomarkers. In this study, we aimed to elucidate the acquisition process and clinical relevance of mismatch repair deficiency (dMMR)-associated mutational signatures.

First, we performed mutational signature analyses across various stages of hepatocarcinogenesis using multi-regional whole-genome sequencing data from 529 samples from 26 patients with or without HCC. Second, multi-omics analysis of an additional 239 HCC samples was conducted. Third, we analysed whole-exome sequencing data from 75 additional HCC samples to elucidate the effect of dMMR-associated signatures on the response to atezolizumab plus bevacizumab.

In the first analysis, dMMR-associated signatures were commonly observed in subclonal mutations in HCC, but were absent in noncancerous liver tissues. The second analysis revealed that a high proportion of dMMR-associated signatures were associated with larger tumour size, advanced tumour stages, upregulation of cell cycle-related genes, and lower expression of the IL6 gene, but not with decreased expression of mismatch repair genes. The third analysis showed that a high proportion of dMMR-associated signatures were significantly associated with better response rates and longer progression-free survival.

Our findings indicate that dMMR-associated signatures can accumulate in HCC without diminished expression levels of mismatch repair proteins, especially during the later stages of tumour progression. They can be a novel biomarker for predicting the efficacy of immunotherapy for HCC.