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

Luan Nguyen, Myrthe Jager, Ruby Lieshout, Petra E de Ruiter, Mauro D Locati, Nicolle Besselink, Bastiaan van der Roest, Roel Janssen, Sander Boymans, Jeroen de Jonge, Jan N M IJzermans, Michail Doukas, Monique M A Verstegen, Ruben van Boxtel, Luc J W van der Laan, Edwin Cuppen, Ewart Kuijk

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1301
JournalCommunications biology
Volume4
Issue number1
DOIs
Publication statusPublished - 18 Nov 2021

Keywords

  • Cholangitis, Sclerosing/genetics
  • Humans
  • Liver/physiology
  • Liver Cirrhosis, Alcoholic/genetics
  • Liver Diseases/genetics
  • Mutagenesis
  • Non-alcoholic Fatty Liver Disease/genetics
  • Organoids/metabolism
  • Precancerous Conditions/genetics
  • Stem Cells/metabolism

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