Hamdane, Nourdine and Juhling, Frank and Crouchet, Emilie and El Saghire, Houssein and Thumann, Christine and Oudot, Marine A. and Bandiera, Simonetta and Saviano, Antonio and Ponsolles, Clara and Suarez, Armando Andres Roca and Li, Shen and Fujiwara, Naoto and Ono, Atsushi and Davidson, Irwin and Bardeesy, Nabeel and Schmidl, Christian and Bock, Christoph and Schuster, Catherine and Lupberger, Joachim and Habersetzer, Francois and Doffoel, Michel and Piardi, Tullio and Sommacale, Daniele and Imamura, Michio and Uchida, Takuro and Ohdan, Hideki and Aikata, Hiroshi and Chayama, Kazuaki and Boldanova, Tujana and Pessaux, Patrick and Fuchs, Bryan C. and Hoshida, Yujin and Zeisel, Mirjam B. and Duong, Francois H. T. and Baumert, Thomas F. (2019) HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response. GASTROENTEROLOGY, 156 (8). 2313-+. ISSN 0016-5085, 1528-0012
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GENE-EXPRESSION; HEPATOCELLULAR-CARCINOMA; VIRUS-INFECTION; CIRRHOSIS; METHYLATION; PREVENTION; FIBROSIS; ENHANCER; Biomarker; Biopsy; Chemoprevention; Sox9 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Apr 2020 05:06 |
| Last Modified: | 08 Apr 2020 05:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26960 |
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