Whole-genome sequencing-based mutational signature analysis reveals the contribution of mismatch repair deficiency to the multistep liver carcinogenesis Poster Award

[Background/Aims] Whole-genome sequencing (WGS) is a powerful tool to unveil the genetic landscape of individual tumors. Although WGS could be applied to clinical practice in the future, it has not been established how to use this big data in clinical setting. Here, we focused on the WGS-based evaluation of mismatch repair deficiency (dMMR), reported as a therapeutic biomarker of cancer immunotherapy. To unveil how dMMR contributes to the multistep hepatocarcinogenesis, we examined WGS data of 793 samples from normal livers to advanced HCCs with clinical information. [Methods] First, 47 multi-regional WGS data from 12 HCCs were phylogenetically analyzed. We determined trunk/private mutations in each tumor, analyzed their mutational signatures and calculated the contribution rates of dMMR to all of the somatic mutations. Noncancerous livers (N=482) of 14 cases without HCC, along with HCCs of different clinical stages (N=262), obtained from public database were also analyzed. [Results] Multi-regional WGS revealed dMMR-associated signatures were significantly enriched in phylogenetically later stage, while click-like and liver-specific signatures were enriched in the trunk mutations. Although noncancerous liver tissues harbor numbers of somatic mutations, we could never find dMMR-associated signatures. [Conclusion] WGS-based mutational signature analysis revealed that dMMR is involved in the somatic mutation accumulation in hepatocarcinogenesis to various degrees, especially at the later stage of progression.