Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease

Normal tissues accumulate genetic changes, but it is unknown if mutations promote clonal expansion of normal cells in response to chronic injury. Exome sequencing of diseased liver samples from 83 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. Also, chromosome 1 and 8 gains were observed, suggesting aneuploidy. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.EGA study EGAS00001003496