HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response

• DOI: 10.1053/j.gastro.2019.02.038
• Publication Date: 2019-03-02T15:36:04Z
• Authors: Nourdine Hamdane; Frank Jühling; Emilie Crouchet; Houssein El Saghire; Christine Thumann; Marine A. Oudot; Simonetta Bandiera; Antonio Saviano; Clara Ponsolles; Armando Andres Ro...; Shen Li; Naoto Fujiwara; Atsushi Ono; Irwin Davidson; Nabeel Bardeesy; Christian Schmidl; Christoph Bock; Catherine Schuster; Joachim Lupberger; François Habersetzer; Michel Doffoël; Tullio Piardi; Daniele Sommacale; Michio Imamura; Takuro Uchida; Hideki Ohdan; Hiroshi Aikata; Kazuaki Chayama; Tujana Boldanova; Patrick Pessaux; Bryan C. Fuchs; Yujin Hoshida; Mirjam B. Zeisel; François H.T. Duong; Thomas F. Baumert
• Keywords: Hepatitis C; Liver disease; Liver Cancer

Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the HCC decreased but not eliminated after a sustained virologic response (SVR) to direct-acting (DAA) agents, and higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect DAA treatment mice humanized livers.We performed genome-wide ChIPmentation-based ChIP-Seq RNA-seq analyses of liver tissues from 6 without HCV (controls), 18 chronic infection, 8 cured by treatment, 13 interferon therapy, 4 B 7 nonalcoholic steatohepatitis Europe Japan. modifications were mapped comparative associated other disease etiologies. uPA/SCID engrafted human hepatocytes create livers given injections HCV-infected serum samples patients; DAAs eradicate virus. Pathways identified integrative pathway validated paired SVR infection.We found induce specific changes H3K27ac, which correlated expression mRNAs proteins. These persisted or interferon-based therapies. Integrative demonstrated cancer risk. Computational increased SPHK1 these findings independent cohort HCV-related cirrhosis (n = 216), subset 21) achieved viral clearance.In analysis we gene HCC. be targeted prevent treated infection.