HCV-induced Epigenetic Changes Associated With Liver Cancer Risk Persist After Sustained Virologic Response
Menée en Europe et au Japon auprès de 50 patients atteints de stéatose hépatique ou d'une hépatite C ou B (6 témoins) et à l'aide d'un modèle murin de foie infecté par le virus de l'hépatite C, cette étude identifie des altérations épigénétiques causées par le virus et associées au risque de carcinome hépatocellulaire après un traitement antiviral d'action directe
Résumé en anglais
Background and 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 reduced but not eliminated following a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and 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 HBV 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 following a sustained virologic response 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 a sustained virologic response 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.
