英国剑桥大学Peter J. Campbell、Matthew Hoare等研究人员合作揭示慢性肝病中代谢基因的趋同体细胞突变。该项研究成果于2021年10月13日在线发表在《自然》杂志上。

研究人员分析了34个肝脏样本中1,590个基因组的体细胞突变，包括健康对照组、酒精相关肝病和非酒精性脂肪肝。29名肝病患者中有7人在FOXO1中发生了突变，FOXO1是胰岛素信号传导的主要转录因子。这些突变影响了该基因内的一个热点，损害了胰岛素介导的FOXO1的核输出。值得注意的是，七名具有FOXO1^S22W热点突变的病人中，有六名表现出趋同的进化，每个病人有多达九个不同的肝细胞克隆独立获得变体。调节肝细胞脂滴代谢的CIDEB，和从游离脂肪酸产生储存三酰甘油的GPAM，也有明显的突变过剩。

研究人员再次观察到频繁的趋同进化：每个病人有CIDEB突变的独立克隆多达14个，每个病人有GPAM突变的独立克隆多达7个。代谢基因的突变分布在肝脏的多个解剖区段，增加了克隆的大小，在酒精相关肝病和非酒精性脂肪肝中都能看到，但在肝细胞癌中很少见。代谢途径的主调控因子是酒精相关和非酒精性脂肪肝中趋同体细胞突变的频繁目标。

据介绍，慢性肝病向肝细胞癌的发展是由影响20-30个癌基因的体细胞突变引起的。与正常肝脏相比，慢性肝病中的体细胞突变负担更重，克隆扩增更大，这使得正向选择能够塑造基因组景观。

附：英文原文

Title: Convergent somatic mutations in metabolism genes in chronic liver disease

Author: Ng, Stanley W. K., Rouhani, Foad J., Brunner, Simon F., Brzozowska, Natalia, Aitken, Sarah J., Yang, Ming, Abascal, Federico, Moore, Luiza, Nikitopoulou, Efterpi, Chappell, Lia, Leongamornlert, Daniel, Ivovic, Aleksandra, Robinson, Philip, Butler, Timothy, Sanders, Mathijs A., Williams, Nicholas, Coorens, Tim H. H., Teague, Jon, Raine, Keiran, Butler, Adam P., Hooks, Yvette, Wilson, Beverley, Birtchnell, Natalie, Naylor, Huw, Davies, Susan E., Stratton, Michael R., Martincorena, Iigo, Rahbari, Raheleh, Frezza, Christian, Hoare, Matthew, Campbell, Peter J.

Issue&Volume: 2021-10-13

Abstract: The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20–30 cancer genes1,2,3,4,5,6,7,8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9,10,11,12,13 than in normal liver13,14,15,16, which enables positive selection to shape the genomic landscape9,10,11,12,13. 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 FOXO1S22W 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 hepatocytes17,18,19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, 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.

DOI: 10.1038/s41586-021-03974-6

Source: https://www.nature.com/articles/s41586-021-03974-6