![]() These signatures are a result of endogenous mutational sources (such as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) activity 22 or homologous recombination deficiency 23, 24), but also microbial impact 25, oxidative stress 26, or anti-cancer therapies 27, 28. Currently, 60 single base substitution (SBS) signatures, 11 double base substitution (DBS) signatures, 18 indel signatures, and 16 structural variation (SV) signatures have been identified 20, 21. We used these catalogs of somatically acquired mutations to perform mutational signature analysis, a powerful computational method for identifying mutational processes that have been active in the life history of cells 20. We previously established a sensitive method to accurately determine all somatic mutations that have been acquired throughout life in individual human adult stem cells of the liver and gastrointestinal tract 19. However, accurate measurements of in vivo induced mutations are required to confirm that accelerated mutagenesis underlies liver tumorigenesis. NASH and PSC are both characterized by chronic inflammation 16, 17, which may cause the production of reactive oxygen and nitrogen species that subsequently induce DNA damage 18. Increased burden of somatic mutations has also been observed in non-alcoholic liver disease 15. Our knowledge on how these environmental conditions drive liver cancer is still incomplete 7.Ĭhronic alcohol consumption is thought to enhance the mutational load through the metabolite acetaldehyde, which has been reported to be directly mutagenic 8 and indirectly through the formation of reactive oxygen species 9, 10, 11, 12, 13, 14. Though less common, chronic inflammation and fibrosis of the biliary tracts, known as primary sclerosing cholangitis (PSC), also confers increased risk of developing both HCC and CCA 6. These factors have also been linked to an increased risk for intrahepatic CCA 5. Several factors have been linked to increased 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. Different subtypes of primary liver cancer can be recognized, of which hepatocellular carcinoma (HCC originating from hepatocytes) and intrahepatic cholangiocarcinoma (CCA originating from cholangiocytes) form the largest groups, together constituting over 85% of all primary liver cancers 2. Liver cancer is the fifth most common cancer worldwide, causing around 720,000 deaths each year 1. 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. 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. 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. ![]() 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). ![]() The mechanism through which liver disease induces tumorigenesis remains unclear, but is thought to occur via increased mutagenesis. Inflammatory liver disease increases the risk of developing primary liver cancer. Precancerous liver diseases do not cause increased mutagenesis in liver stem cells
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