Precancerous liver diseases do not cause increased mutagenesis in liver stem cells

• DOI: 10.1038/s42003-021-02839-y
• Publication Date: 2021-11-18T11:06:20Z
• Authors: Luan Nguyen; Myrthe Jager; Ruby Lieshout; Petra E. de Ruiter; Mauro D. Locati; Nicolle Besselink; Bastiaan van der ...; Roel Janssen; Sander Boymans; Jeroen de Jonge; Jan N. M. IJzermans; Michail Doukas; Monique M. A. Ver...; Ruben van Boxtel; Luc J. W. van der...; Edwin Cuppen; Ewart Kuijk
• Keywords: 0301 basic medicine; Liver Cirrhosis, Alcoholic/genetics; QH301-705.5; Cholangitis, Sclerosing; Non-alcoholic Fatty Liver Disease/genetics; Article; 03 medical and health sciences; Cholangitis, Sclerosing/genetics; Liver/physiology; SDG 3 - Good Health and Well-being; Liver Cirrhosis, Alcoholic; Non-alcoholic Fatty Liver Disease; Precancerous Conditions/genetics; Organoids/metabolism; Journal Article; Liver Diseases/genetics; Humans; Biology (General); Stem Cells/metabolism; Research Support, Non-U.S. Gov't; Liver Diseases; Stem Cells; 3. Good health; Organoids; Liver; Mutagenesis; Precancerous Conditions

AbstractInflammatory 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.