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

与非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）相关的脂肪性肝细胞变性是西方工业国家慢性肝病最常见的原因。据估计，NAFLD和NASH的患病率为成人人口的30-40%，与肥胖、糖尿病和代谢综合征有直接关系。NAFLD可发展为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，肝癌发生的风险显著增加。越来越多的肝移植是由于nash引起的肝硬化或肝癌。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，没有肝硬化的脂肪性肝病必须被视为潜在的癌前病变。作为癌前病变的脂肪变性肝细胞内的基因组失衡以及NAFLD向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有助于了解代谢应激相关的遗传失衡。分子靶标，如癌基因和肝脏特异性细胞周期或增殖调节因子（TP53, HER2, Cyclin D1, C-Myc， MET， TERT）将在所谓的“共同脆弱位点”标记（FHIT和WWOX）中进行研究。计划中的多重荧光原位杂交（FISH）允许对患病肝细胞进行靶向单细胞分析，并在此基础上重建肿瘤发展过程中的系统发育树。本项目的研究结果有望解答以下科学问题：1)脂肪肝细胞变性中，所列8个基因组标记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发展过程中是否存在一系列基因组失衡？

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?