Chronic liver disease is associated with metabolic dysregulation, liver failure and hepatocellular carcinoma. We analysed somatic mutations from 1202 genomes across 32 liver samples, including normal controls, alcohol-related and non-alcoholic fatty liver disease. Five of 27 patients with liver disease carried hotspot driver mutations in FOXO1, the major transcription factor downstream of insulin signalling. FOXO1 mutations were independently acquired by up to 5 distinct clones within the same patient’s sample, and impaired insulin-mediated nuclear export of FOXO1. GPAM, which produces storage triacylglycerol from dietary calories, also had significant excess of mutations, similarly exhibiting convergent evolution within biopsies. Telomer... (Read more)