科学家探究肝硬化过程中突变发生
作者：
小柯机器人 发布时间：2019/10/24 14:36:19
英国剑桥大学Peter J. Campbell和Matthew Hoare等研究人员合作，探究了健康和肝硬化患者肝脏的体细胞突变和克隆动态变化。相关论文发表在2019年10月24日出版的《自然》杂志上。
通过对来自5个正常肝和9个肝硬化肝的100–500个肝细胞的482个显微解剖区域的全基因组进行测序，研究人员发现，与正常肝相比，肝硬化肝具有更高的突变负担。尽管在正常肝细胞中很少见，但包括肝硬变在内的结构变异在肝硬化中尤为突出。驱动程序突变，例如点突变和结构变异，影响了1-5％的克隆。肝硬化发生直径为毫米的克隆扩增，克隆被包围在再生结节周围的纤维化带所隔离。在非恶性肝细胞和肝癌中，一些突变特征是普遍的，并且具有相同的活性。与慢性肝病相比，有些在肝癌中的活性明显更高，其他原因是由于外源性暴露引起的。
由于克隆特异性和微环境作用力，每个病人中肝硬化结节之间的外源性信号活性变化多达十倍。同步肝癌表现出与背景肝硬化肝相同的突变特征，但负担更高。体细胞突变记载了从健康到疾病发展过程中肝脏组织的暴露、毒性、再生和克隆结构。
据了解，慢性肝病的最常见原因是过量饮酒、病毒性肝炎和非酒精性脂肪肝，其临床严重范围从肝炎到肝硬化、肝衰竭或肝细胞癌。肝癌的基因组表现出多样化的突变特征，导致超过30种癌症基因的反复突变。正常肝脏的干细胞突变负荷低，且特征多样性有限，这表明肝癌的复杂性是在发展为慢性肝病和随后的恶性转化过程中出现的。
附：英文原文
Title:Somatic mutations and clonal dynamics in healthy and cirrhotic human liver
Author:Simon F. Brunner, Nicola D. Roberts, Luke A. Wylie, Luiza Moore, Sarah J. Aitken, Susan E. Davies, Mathijs A. Sanders, Pete Ellis, Chris Alder, Yvette Hooks, Federico Abascal, Michael R. Stratton, Inigo Martincorena, Matthew Hoare & Peter J. Campbell
Issue&Volume:Volume 574 Issue 7779
Abstract:
The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1,2,3,4,5,6,7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100–500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1–5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others—arising from exogenous exposures—were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.
DOI:10.1038/s41586-019-1670-9
