Chromosomale Instabilität in nicht-alcoholischer Fettleber (NAFL), nicht-alkoholischer Steatohepatitis (NASH) und damit assoziierten Leberzellkarzinomen.

• Antragstellerin: Dr. Juliane Friemel
• Fachliche Zuordnung: Pathologie ; Allgemeine Genetik und funktionelle Genomforschung
• Förderung: Förderung von 2016 bis 2017
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 326130116

• Erstellungsjahr: 2017

Zusammenfassung der Projektergebnisse

Multiplex single-cell FISH analysis is an approach to fine-map spatially restricted numerical abberrations in NASH-induced HCC and ist precursor lesions. Different degrees of genomic instability and a broad spectrum of numerical aberrations and polyploidization in HCCs of patients with clinical background of diabetes, obesity and/or manifest nonalcoholic fatty liver disease were detected. The most frequently found numerical aberrations were MYC (8q24.21) amplification, loss of TP53 (17p13.1) and gain of TERT (5p15.33). Within individual HCC, tumor cell diversification was evident, e.g. we observed cases with major clones that comprised up to 80% of the cell population, other cases were characterized by multiclonality and a wide variety of FISH signal patterns indicating high genomic instability. Statistical analysis yielded a significant correlation of chromosomal instability index with tumor grade (p=0.03) but not with other histopathological parameters such as tumor stage, size or angioinvasion. For the first time we show that initial chromosomal aberrations already are detectable at the state of NAFLD / NASH. Liver biopsies with nonacloholic fatty liver disease were histopathologicallly scored according to the NAS score yielding 5 cases with NAFLD and 2 cases with borderline NASH. Aberrant FISH signal patterns such as WWOX loss, TERT gain and HER2 loss did not exceed 10% of 300 reviewed cells per case. An unexpected result was that chromosomal aberrations were also present in polyploid hepatocytes (tetraploid and octoploid cells). Varying extent of polyploidization with and without chromosomal aberrations was observed throughout all cases. In NAFLD/NASH cases, a correlation with macrosteatosis, fibrosis or NAS score could not be detected, although it is suggested in the literature that polyploidization might be an adaptive phenotype to liver stress.

Projektbezogene Publikationen (Auswahl)

• Jahrestagung “Deutsche Gesellschaft Pathologie” 2017: Genomic instability and aneuploidy of hepatocellular carcinomas in patients with metabolic risk factors
  Juliane Friemel