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

Nourdine Hamdane, Frank Jühling, Emilie Crouchet, Houssein El Saghire, Christine Thumann, Marine A. Oudot, Simonetta Bandiera, Antonio Saviano, Clara Ponsolles, Armando Andres Roca Suarez, Shen Li, Naoto Fujiwara, Atsushi Ono, Irwin Davidson, Nabeel Bardeesy, Christian Schmidl, Christoph Bock, Catherine Schuster, Joachim Lupberger, François HabersetzerMichel 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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2313-2329.e7
JournalGastroenterology
Volume156
Issue number8
DOIs
StatePublished - Jun 2019

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Liver Neoplasms
Epigenomics
Hepacivirus
Virus Diseases
Hepatocellular Carcinoma
Antiviral Agents
Chronic Hepatitis C
Liver
Sustained Virologic Response
Interferons
Therapeutics
Fibrosis
Genome
SCID Mice
Chronic Hepatitis B
Infection Control
Hepatitis B virus
Liver Diseases
Hepatocytes
Japan

Keywords

  • Biomarker
  • Biopsy
  • Chemoprevention
  • Sox9

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Hamdane, N., Jühling, F., Crouchet, E., El Saghire, H., Thumann, C., Oudot, M. A., ... Baumert, T. F. (2019). HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response. Gastroenterology, 156(8), 2313-2329.e7. https://doi.org/10.1053/j.gastro.2019.02.038

HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response. / Hamdane, Nourdine; Jühling, Frank; Crouchet, Emilie; El Saghire, Houssein; Thumann, Christine; Oudot, Marine A.; Bandiera, Simonetta; Saviano, Antonio; Ponsolles, Clara; Roca Suarez, Armando Andres; Li, Shen; Fujiwara, Naoto; Ono, Atsushi; Davidson, Irwin; Bardeesy, Nabeel; Schmidl, Christian; Bock, Christoph; Schuster, Catherine; Lupberger, Joachim; Habersetzer, François; Doffoël, Michel; Piardi, Tullio; Sommacale, Daniele; Imamura, Michio; Uchida, Takuro; Ohdan, Hideki; Aikata, Hiroshi; Chayama, Kazuaki; Boldanova, Tujana; Pessaux, Patrick; Fuchs, Bryan C.; Hoshida, Yujin; Zeisel, Mirjam B.; Duong, François H.T.; Baumert, Thomas F.

In: Gastroenterology, Vol. 156, No. 8, 06.2019, p. 2313-2329.e7.

Research output: Contribution to journalArticle

Hamdane, N, Jühling, F, Crouchet, E, El Saghire, H, Thumann, C, Oudot, MA, Bandiera, S, Saviano, A, Ponsolles, C, Roca Suarez, AA, Li, S, Fujiwara, N, Ono, A, Davidson, I, Bardeesy, N, Schmidl, C, Bock, C, Schuster, C, Lupberger, J, Habersetzer, F, Doffoël, M, Piardi, T, Sommacale, D, Imamura, M, Uchida, T, Ohdan, H, Aikata, H, Chayama, K, Boldanova, T, Pessaux, P, Fuchs, BC, Hoshida, Y, Zeisel, MB, Duong, FHT & Baumert, TF 2019, 'HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response', Gastroenterology, vol. 156, no. 8, pp. 2313-2329.e7. https://doi.org/10.1053/j.gastro.2019.02.038
Hamdane, Nourdine ; Jühling, Frank ; Crouchet, Emilie ; El Saghire, Houssein ; Thumann, Christine ; Oudot, Marine A. ; Bandiera, Simonetta ; Saviano, Antonio ; Ponsolles, Clara ; Roca Suarez, Armando Andres ; Li, Shen ; Fujiwara, Naoto ; Ono, Atsushi ; Davidson, Irwin ; Bardeesy, Nabeel ; Schmidl, Christian ; Bock, Christoph ; Schuster, Catherine ; Lupberger, Joachim ; Habersetzer, François ; Doffoël, Michel ; Piardi, Tullio ; Sommacale, Daniele ; Imamura, Michio ; Uchida, Takuro ; Ohdan, Hideki ; Aikata, Hiroshi ; Chayama, Kazuaki ; Boldanova, Tujana ; Pessaux, Patrick ; Fuchs, Bryan C. ; Hoshida, Yujin ; Zeisel, Mirjam B. ; Duong, François H.T. ; Baumert, Thomas F. / HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response. In: Gastroenterology. 2019 ; Vol. 156, No. 8. pp. 2313-2329.e7.
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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.",
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TY - JOUR

T1 - HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response

AU - Hamdane, Nourdine

AU - Jühling, Frank

AU - Crouchet, Emilie

AU - El Saghire, Houssein

AU - Thumann, Christine

AU - Oudot, Marine A.

AU - Bandiera, Simonetta

AU - Saviano, Antonio

AU - Ponsolles, Clara

AU - Roca Suarez, Armando Andres

AU - Li, Shen

AU - Fujiwara, Naoto

AU - Ono, Atsushi

AU - Davidson, Irwin

AU - Bardeesy, Nabeel

AU - Schmidl, Christian

AU - Bock, Christoph

AU - Schuster, Catherine

AU - Lupberger, Joachim

AU - Habersetzer, François

AU - Doffoël, Michel

AU - Piardi, Tullio

AU - Sommacale, Daniele

AU - Imamura, Michio

AU - Uchida, Takuro

AU - Ohdan, Hideki

AU - Aikata, Hiroshi

AU - Chayama, Kazuaki

AU - Boldanova, Tujana

AU - Pessaux, Patrick

AU - Fuchs, Bryan C.

AU - Hoshida, Yujin

AU - Zeisel, Mirjam B.

AU - Duong, François H.T.

AU - Baumert, Thomas F.

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - Biomarker

KW - Biopsy

KW - Chemoprevention

KW - Sox9

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