Chromosomal instability in nonalcoholic steatohepatitis (NASH) induced hepatocellular carcinoma and its precursor lesion nonalcoholic fatty liver disease (NAFLD).

非酒精性脂肪性肝炎（NASH）诱发的肝细胞癌及其前驱病变非酒精性脂肪性肝病（NAFLD）中的染色体不稳定。

• 批准号: 326130116
• 负责人: Dr. Juliane Friemel
• 金额: --
• 依托单位: Leibniz-Institut für Präventionsforschung und Epidemiologie - BIPS GmbH
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326130116?language=en
• 关键词: Chromosomal; instability; nonalcoholic; steatohepatitis; NASH

Fat-induced liver cell degeneration related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is the most common cause for chronic liver diseases in western industrial nations. The estimated prevalence of NAFLD and NASH is 30-40% of the adult population and there is a direct relationship with obesity, diabetes mellitus and metabolic syndrome. NAFLD can progress to NASH, to NASH-induced liver cirrhosis or NASH-induced liver cancer. Epidemiological studies show substantial risk increase of liver cancer development in the background of NAFLD and NASH. An increasing number of liver transplantations is performed due to NASH-induced cirrhosis or liver cancer. While liver cancer related to alcohol and hepatitis usually develops on the background of cirrhosis, there is evidence that fatty liver disease alone, without liver cirrhosis, has to be considered as a potential precancerous lesion. The genomic imbalances within a fatty degenerated liver cell as precancerous lesion and the progression from NAFLD to NASH-associated hepatocellular carcinoma have so far not been systematically analyzed. Gene-specific fine mapping of chromosomal instability in NASH-associated liver cancer and its precursor lesions would allow insight in metabolic stress-associated genetic imbalances. Molecular targets such as oncogenes and liverspecific cell-cycle or proliferation regulators (TP53, HER2, Cyclin D1, C-Myc, MET, TERT) will be investigated among the so called "common fragile site" markers (FHIT and WWOX).The planned multiplex fluorescence in situ hybridization (FISH) allows targeted single cell analysis in diseased liver cells, and based on that the reconstruction of phylogenetic trees during tumor development. Results of this project are expected to enable us to answer the following scientific questions: 1) Are there early genomic imbalances at the listed 8 genomic marker in fatty liver cell degeneration? 2) Does a sequence of genomic imbalances exist during clonal evolution and progression from fatty liver disease to liver cancer?

与非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）相关的脂肪诱导的肝细胞变性是西方工业国家慢性肝病的最常见原因。NAFLD和NASH的估计患病率为成年人群的30-40%，并且与肥胖、糖尿病和代谢综合征直接相关。NAFLD可以进展为NASH、NASH诱导的肝硬化或NASH诱导的肝癌。流行病学研究表明，在NAFLD和NASH的背景下，肝癌发展的风险显著增加。越来越多的肝移植是由于NASH诱导的肝硬化或肝癌而进行的。 虽然与酒精和肝炎相关的肝癌通常在肝硬化的背景下发展，但有证据表明，没有肝硬化的脂肪肝疾病单独被认为是潜在的癌前病变。脂肪变性肝细胞作为癌前病变的基因组失衡以及从NAFLD到NASH相关肝细胞癌的进展迄今尚未得到系统分析。NASH相关肝癌及其前体病变中染色体不稳定性的基因特异性精细定位将允许洞察代谢应激相关的遗传失衡。分子靶点，如癌基因和肝脏特异性细胞周期或增殖调节因子将在所谓的“共同脆性位点”标志物中研究TP 53、HER 2、细胞周期蛋白D1、C-Myc、MET、TERT计划中的多重荧光原位杂交（FISH）允许在患病肝细胞中进行靶向单细胞分析，并在此基础上重建肿瘤发生发展的系统发育树。该项目的结果预计将使我们能够回答以下科学问题：1）在脂肪肝细胞变性中列出的8个基因组标志物是否存在早期基因组失衡？2)从脂肪肝到肝癌的克隆进化和进展过程中是否存在一系列基因组不平衡？