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

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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?