Mutational impact in liver stem cells under precancerous alcoholic liver, NASH and PSC disease conditions

Inflammatory liver disease increases risk of developing liver cancer. The mechanism through which liver disease induces tumorigenesis remains unclear, but is thought to occur via increased mutagenesis. Here, we performed whole-genome sequencing on clonal stem cell organoid lines derived from explanted diseased liver cells from patients with chronic alcohol consumption, non-alcoholic steatohepatitis NASH, and primary sclerosing cholangitis PSC. Surprisingly, we find that these precancerous liver disease conditions do not result in a detectable increased accumulation of mutations, nor altered mutation types in normal stem cells in the liver, which contrasts with typical mutational signatures found in liver tumors. Our findings argue against the idea that liver disease drives tumorigenesis via a direct mechanism of induced mutagenesis, and suggests that the transition from healthy to cancerous liver cells likely occurs through other mechanisms, such as changes to the microenvironment that facilitate the outgrowth of precancerous cells that would normally be suppressed. Increased proliferation of such cells would result in an increase in mutations associated with endogenous mutational processes, which we indeed observed when examining the early stage mutations in a hepatocellular carcinoma.EGA study EGAS00001005384