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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

7 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)1301
TijdschriftCommunications biology
Nummer van het tijdschrift1
StatusGepubliceerd - 18 nov. 2021


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