PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk. [Display omitted] •Sequencing of cirrhotic liver tissues revealed recurrent somatic mutations in PKD1•PKD1 loss promotes regeneration, but not cancer development•PKD1 loss protects against fatty liver disease•In hepatocytes, Pkd1 loss increased insulin sensitivity and mTOR signaling Zhu et al. show that somatic mutations in PKD1 are selected for in chronically damaged livers because they promote clone and tissue fitness without driving carcinogenesis.