Genomic approaches to uncover clonal structure and oncogenic potential of liver cirrhosis

HCC frequently and recurrently develops in the background of liver cirrhosis. Although progress in sequencing technologies enabled us to understand the landscape of genetic alterations in HCC tissues, genetic aberrations latently accumulated in the cirrhotic liver with high risk of hepatocarcinogenesis have not been elucidated. In the current study, we aimed to uncover clonal structure and oncogenic potential of liver cirrhosis by determining the genomic aberrations latently accumulated in the cirrhotic liver. For this purpose, we extracted DNA from 205 biopsy samples manually obtained from the cirrhotic livers with or without HCC development, and subsequently applied to the whole-exome sequencing and targeted sequencing of the representative HCC-associated genes. Whole-exome sequencing revealed that almost all samples examined possessed clonal population of hepatocytes with a variety of somatic mutations. The mutation signature determined in the cirrhotic liver was characterized by a predominance of C>T, followed by T>C and C>A mutations, which were similar to those of HCC tissues. Targeted sequencing analyses showed that somatic mutations of HCC-associated genes including TP53, CTNNB1 and ARID1A were detectable in 47 of 205 samples (23%), while TERT promoter mutation was not found in any cirrhotic samples examined. In conclusion,our findings suggested that liver cirrhosis possessed a subset of cell population with putative oncogenic mutations, providing the molecular basis of multicentric tumorigenesis.