Mutational impact of chronic alcohol use on stem cells in cirrhotic liver
Myrthe Jager, Ewart Kuijk, Ruby Lieshout, Mauro D. Locati, Nicolle Besselink, Bastiaan van der Roest, Roel Janssen, Sander Boymans, Jeroen de Jonge, Jan N.M. IJzermans, Michael Doukas, Monique M.A. Verstegen, Ruben van Boxtel, Luc J.W. van der Laan, Edwin Cuppen
Date Received: 10th July 19
Excessive alcohol consumption increases the risk of developing liver cancer, but the mechanism through which alcohol drives carcinogenesis is as yet unknown. Here, we determined the mutational consequences of chronic alcohol use on the genome of human liver stem cells prior to cancer development. No change in base substitution rate or spectrum could be detected. Analysis of the trunk mutations in an alcohol-related liver tumor by multi-site whole-genome sequencing confirms the absence of specific alcohol-induced mutational signatures driving the development of liver cancer. However, we did identify an enrichment of nonsynonymous base substitutions in cancer genes in stem cells of the cirrhotic livers, such as recurrent nonsense mutations in PTPRK that disturb Epidermal Growth Factor (EGF)-signaling. Our results thus suggest that chronic alcohol use does not contribute to carcinogenesis through altered mutagenicity, but instead induces microenvironment changes which provide a ‘fertile ground’ for selection of cells with oncogenic mutations.
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.