The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20–30 cancer genes^{1,2,3,4,5,6,7,8}. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease^{9,10,11,12,13} than in normal liver^13,14,15,16, which enables positive selection to shape the genomic landscape^{9,10,11,12,13}. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1^S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes^17,18,19, and GPAM, which produces storage triacylglycerol from free fatty acids^20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.

慢性肝病进展为肝细胞癌是由影响 20-30 个癌症基因的体细胞突变引起的^{1,2,3,4,5,6,7,8} 。与正常肝脏相比，慢性肝病^{9,10,11,12,13}的体细胞突变负担更高，克隆扩张更大^13,14,15,16 ，这使得正向选择能够塑造基因组景观^{9,10,11, 12,13} 。在这里，我们分析了 34 个肝脏样本中 1,590 个基因组的体细胞突变，包括健康对照、酒精相关性肝病和非酒精性脂肪肝病。 29 名肝病患者中有 7 名存在FOXO1突变，FOXO1 是胰岛素信号传导的主要转录因子。这些突变影响了基因内的单个热点，损害了胰岛素介导的 FOXO1 核输出。值得注意的是，7 名携带FOXO1 ^S22W热点突变的患者中有 6 名表现出趋同进化，每个患者多达 9 个不同的肝细胞克隆独立获得变异。 CIDEB调节肝细胞中的脂滴代谢^17,18,19 ，而GPAM则从游离脂肪酸产生储存三酰甘油^20,21 ，也有显着过量的突变。我们再次观察到频繁的趋同进化：每个具有CIDEB突变的患者最多有 14 个独立克隆，每个具有GPAM突变的患者最多有 7 个克隆。 代谢基因突变分布在肝脏的多个解剖部分，克隆大小增加，在酒精相关性肝病和非酒精性脂肪肝病中都可见，但在肝细胞癌中很少见。代谢途径的主要调节因子是酒精相关性和非酒精性脂肪肝疾病中趋同体细胞突变的常见目标。