Z Gastroenterol 2007; 45 - A2_32
DOI: 10.1055/s-2007-967822

Telomere shortening and p21-checkpoint inactivation characterize multistep hepatocarcinogenesis in humans

RR Plentz 1, A Lechel 2, YN Park 3, H Kim 4, F Nellessen 2, BHE Langkopf 2, L Wilkens 5, MP Manns 2, A Destro 6, B Fiamengo 6, M Roncalli 6, KL Rudolph 2
  • 1MGH Cancer Center, Boston, USA
  • 2Abt. Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover
  • 3Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
  • 4Department of Pathology, Seoul National University Bundang Hospital, Gyeonggi-do, Korea
  • 5Abt. für Zell- und Molekularpathologie, Medizinische Hochschule Hannover, Hannover
  • 6Department of Pathology, University of Milan and Humanitas Clinical Institute of Rozzano, Milan, Italy

Telomere shortening and DNA-damage-checkpoint inactivation have been identified as molecular hallmarks characterizing early carcinogenesis in humans but it is unknown, whether these molecular features coincide at specific stages of multistep carcinogenesis in humans.

The preneoplasia-carcinoma sequence of human hepatocellular carcinoma (HCC) is not well defined. Small cell changes (SCC) and large cell changes (LCC) are possible precursor lesions. The molecular characterization of these potential precursor lesions could help to define multistep hepatocarcinogenesis in humans.

We analyzed hepatocellular telomere length and labeling index (LI) of the cell cycle inhibitor p21 on liver biopsies of patients with chronic liver disease (n=24) that showed different precursor lesions and/or HCC: liver cirrhosis (n=22), LCC (n=24), SCC (n=10), and HCC (n=12). We found a decrease in telomere length in non dysplastic cirrhotic liver compared to normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres followed by SCC and LCC. In line with the telomere hypothesis of cirrhosis development, hepatocytes showed an increased p21-LI at the cirrhosis stage, which remained elevated in the vast majority of LCC. Most SCC and HCC showed a strongly reduced p21-LI.

Our data suggest that both LCC and SCC represent clonal expansion of hepatocytes with shortened telomeres and indicate that telomere shortening and p21-checkpoint inactivation occur at a defined stage during human multistep hepatocarcinogenesis and suggest that SCC represent more advanced precursor lesions compared to LCC.

Multistep Hepatocarcinogenesis - Telomere Shortening - p21