Abstract
Inflammatory liver disease increases the risk of developing primary 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 clonally expanded single liver stem cells cultured as intrahepatic cholangiocyte organoids (ICOs) from patients with alcoholic cirrhosis, 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 individual liver stem cells. This finding contrasts with the mutational load and typical mutational signatures reported for liver tumors, and argues against the hypothesis that liver disease drives tumorigenesis via a direct mechanism of induced mutagenesis. Disease conditions in the liver may thus act through indirect mechanisms to drive the transition from healthy to cancerous cells, such as changes to the microenvironment that favor the outgrowth of precancerous cells.
Highlights
Inflammatory liver disease increases the risk of developing primary liver cancer
Several factors have been linked to increased hepatocellular carcinoma (HCC) risk, including chronic alcohol consumption[3], as well as metabolic associated fatty liver disease (MAFLD), and its more progressive form nonalcoholic steatohepatitis (NASH), which can be caused by obesity, diabetes, drugs/medication and metabolic conditions[4]
Cholangiocytes can be grown as intrahepatic cholangiocyte organoids (ICO)[31] that show long-term self-renewal, differentiation, and engraftment in mouse and rat models of liver failure[32,33]
Summary
Inflammatory liver disease increases the risk of developing primary liver cancer. The mechanism through which liver disease induces tumorigenesis remains unclear, but is thought to occur via increased mutagenesis. We find that these precancerous liver disease conditions do not result in a detectable increased accumulation of mutations, nor altered mutation types in individual liver stem cells This finding contrasts with the mutational load and typical mutational signatures reported for liver tumors, and argues against the hypothesis that liver disease drives tumorigenesis via a direct mechanism of induced mutagenesis. We aim to identify the mutational processes that contribute to the precancerous state in common human liver diseases To achieve this goal, we have studied the accumulation of mutations in individual stem cells derived from livers of patients with alcoholic cirrhosis, NASH and PSC who received a liver transplantation. Our findings suggest that environmental conditions drive liver tumorigenesis through means other than by increasing mutagenesis
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