@article{49c592a50cae4d5dbcd1c66e36059903,
title = "HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response",
abstract = "Background & Aims: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk for HCC is decreased but not eliminated after a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and the risk is higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect risk for HCC after DAA treatment in patients and mice with humanized livers. Methods: We performed genome-wide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissues from 6 patients without HCV infection (controls), 18 patients with chronic HCV infection, 8 patients with chronic HCV infection cured by DAA treatment, 13 patients with chronic HCV infection cured by interferon therapy, 4 patients with chronic hepatitis B virus infection, and 7 patients with nonalcoholic steatohepatitis in Europe and Japan. HCV-induced epigenetic modifications were mapped by comparative analyses with modifications associated with other liver disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice with humanized livers and given injections of HCV-infected serum samples from patients; mice were given DAAs to eradicate the virus. Pathways associated with HCC risk were identified by integrative pathway analyses and validated in analyses of paired HCC tissues from 8 patients with an SVR to DAA treatment of HCV infection. Results: We found chronic HCV infection to induce specific genome-wide changes in H3K27ac, which correlated with changes in expression of mRNAs and proteins. These changes persisted after an SVR to DAAs or interferon-based therapies. Integrative pathway analyses of liver tissues from patients and mice with humanized livers demonstrated that HCV-induced epigenetic alterations were associated with liver cancer risk. Computational analyses associated increased expression of SPHK1 with HCC risk. We validated these findings in an independent cohort of patients with HCV-related cirrhosis (n = 216), a subset of which (n = 21) achieved viral clearance. Conclusions: In an analysis of liver tissues from patients with and without an SVR to DAA therapy, we identified epigenetic and gene expression alterations associated with risk for HCC. These alterations might be targeted to prevent liver cancer in patients treated for HCV infection.",
keywords = "Biomarker, Biopsy, Chemoprevention, Sox9",
author = "Nourdine Hamdane and Frank J{\"u}hling and Emilie Crouchet and {El Saghire}, Houssein and Christine Thumann and Oudot, {Marine A.} and Simonetta Bandiera and Antonio Saviano and Clara Ponsolles and {Roca Suarez}, {Armando Andres} and Shen Li and Naoto Fujiwara and Atsushi Ono and Irwin Davidson and Nabeel Bardeesy and Christian Schmidl and Christoph Bock and Catherine Schuster and Joachim Lupberger and Fran{\c c}ois Habersetzer and Michel Doffo{\"e}l and Tullio Piardi and Daniele Sommacale and Michio Imamura and Takuro Uchida and Hideki Ohdan and Hiroshi Aikata and Kazuaki Chayama and Tujana Boldanova and Patrick Pessaux and Fuchs, {Bryan C.} and Yujin Hoshida and Zeisel, {Mirjam B.} and Duong, {Fran{\c c}ois H.T.} and Baumert, {Thomas F.}",
note = "Funding Information: Funding This work was supported by the ARC (Paris) and the Institut Hospitalo-Universitaire (Strasbourg; TheraHCC IHUARC IHU201301187 to Thomas F. Baumert), the Foundation of the University of Strasbourg and Roche Institute (HEPKIN to Thomas F. Baumert and Yujin Hoshida), the Agence Nationale de Recherches sur le Sida et les H{\'e}patites Virales (2017/1633 to Thomas F. Baumert), the U.S. Department of Defense (W81XWH-16-1-0363 to Yujin Hoshida and Thomas F. Baumert), the Canc{\'e}rop{\^o}le du Grand-Est (AAP Emergence 2017 to Joachim Lupberger), the National Institutes of Health (DK099558 to Yujin Hoshida), and the Research Program on Hepatitis from the Japan Agency for Medical Research and Development, AMED (17fk0210104h0001 to Kazuaki Chayama). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667273 (HEPCAR to Thomas F. Baumert and Joachim Lupberger). This project has received funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Program under grant 671231 (HEPCIR to Thomas F. Baumert and Yujin Hoshida). This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS, and PLAN CANCER 2014–2019 and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the Future Program, the French National Cancer Institute, and INSERM. Funding This work was supported by the ARC (Paris) and the Institut Hospitalo-Universitaire (Strasbourg; TheraHCC IHUARC IHU201301187 to Thomas F. Baumert), the Foundation of the University of Strasbourg and Roche Institute (HEPKIN to Thomas F. Baumert and Yujin Hoshida), the Agence Nationale de Recherches sur le Sida et les H{\'e}patites Virales ( 2017/1633 to Thomas F. Baumert), the U.S. Department of Defense ( W81XWH-16-1-0363 to Yujin Hoshida and Thomas F. Baumert), the Canc{\'e}rop{\^o}le du Grand-Est (AAP Emergence 2017 to Joachim Lupberger), the National Institutes of Health ( DK099558 to Yujin Hoshida), and the Research Program on Hepatitis from the Japan Agency for Medical Research and Development, AMED ( 17fk0210104h0001 to Kazuaki Chayama). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667273 (HEPCAR to Thomas F. Baumert and Joachim Lupberger). This project has received funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Program under grant 671231 (HEPCIR to Thomas F. Baumert and Yujin Hoshida). This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS, and PLAN CANCER 2014–2019 and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the Future Program, the French National Cancer Institute, and INSERM. We acknowledge the Centre de Ressources Biologiques (Biological Resource Centre; Strasbourg, France) for the management of patient-derived liver tissues. We acknowledge the work of the IGBMC high-throughput sequencing facility and the Quantitative Genomics Facility at the Department of Biosystems Science and Engineering at the scientific central facilities of ETH Zurich. The IGBMC high-throughput sequencing facility is a member of the France G{\'e}nomique consortium (ANR10-INBS-09-08). The laboratory of Irwin Davidson is an {\'e}quipe labellis{\'e}e of the Ligue Nationale contre le Cancer. Author contributions: Thomas F. Baumert initiated and coordinated the study. Thomas F. Baumert, Nourdine Hamdane, Frank J{\"u}hling, Mirjam B. Zeisel, Yujin Hoshida, and Bryan C. Fuchs designed experiments and analyzed data. Nourdine Hamdane, Emilie Crouchet, Christine Thumann, Marine A. Oudot, Clara Ponsolles, Armando Andres Roca Suarez, and Shen Li performed experiments. Frank J{\"u}hling performed computational analyses. Nabeel Bardeesy contributed to the concept and approach of the study. Christian Schmidl and Christoph Bock performed sequencing of ChIPmentation experiments. Irwin Davidson, Houssein El Saghire, Antonio Saviano, Naoto Fujiwara, Catherine Schuster, Atsushi Ono, and Yujin Hoshida analyzed data. Patrick Pessaux, Michio Imamura, Takuro Uchida, Hideki Ohdan, Hiroshi Aikata, Kazuaki Chayama, Tullio Piardi, Daniele Sommacale, Fran{\c c}ois Habersetzer, Michel Doffo{\"e}l, and Tujana Boldanova provided clinical liver tissue samples. Nourdine Hamdane, Frank J{\"u}hling, Fran{\c c}ois H.T. Duong, Bryan C. Fuchs, Joachim Lupberger, Mirjam B. Zeisel, and Thomas F. Baumert wrote the manuscript. Funding This work was supported by the ARC (Paris) and the Institut Hospitalo-Universitaire (Strasbourg; TheraHCC IHUARC IHU201301187 to Thomas F. Baumert), the Foundation of the University of Strasbourg and Roche Institute (HEPKIN to Thomas F. Baumert and Yujin Hoshida), the Agence Nationale de Recherches sur le Sida et les H{\'e}patites Virales ( 2017/1633 to Thomas F. Baumert), the U.S. Department of Defense ( W81XWH-16-1-0363 to Yujin Hoshida and Thomas F. Baumert), the Canc{\'e}rop{\^o}le du Grand-Est (AAP Emergence 2017 to Joachim Lupberger), the National Institutes of Health ( DK099558 to Yujin Hoshida), and the Research Program on Hepatitis from the Japan Agency for Medical Research and Development, AMED ( 17fk0210104h0001 to Kazuaki Chayama). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement 667273 (HEPCAR to Thomas F. Baumert and Joachim Lupberger). This project has received funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Program under grant 671231 (HEPCIR to Thomas F. Baumert and Yujin Hoshida). This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS, and PLAN CANCER 2014–2019 and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the Future Program, the French National Cancer Institute, and INSERM. Publisher Copyright: {\textcopyright} 2019 AGA Institute",
year = "2019",
month = jun,
doi = "10.1053/j.gastro.2019.02.038",
language = "English (US)",
volume = "156",
pages = "2313--2329.e7",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "8",
}