Risk for Liver Cancer Associated With HCV-Induced Epigenetic Changes

Epigenetic and gene expression alterations associated with risk for hepatocellular carcinoma (HCC) have been identified in an analysis of liver tissue obtained from patients with hepatitis C virus (HCV) infection, both with and without a sustained virologic response (SVR) to direct-acting antiviral (DAA) therapy. A genome-wide study of liver tissue obtained from European and Japanese patients was conducted. Results of the analysis were published in Gastroenterology.

The investigators sought to explore HCV-induced epigenetic modifications that might affect the risk for HCC after DAA treatment in patients and mice with humanized livers. They performed genome-wide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissue from the following groups: patients with chronic HCV infection (n=18), patients with chronic HCV infection that was cured by DAA therapy (n=8), patients with chronic HCV infection that was cured by interferon therapy (n=13), patients with chronic hepatitis B infection (n=4), patients with nonalcoholic steatohepatitis (n=7), and patients without HCV infection (controls; n=6).

HCV-induced epigenetic modifications were mapped via the use of comparative analyses with modifications that were related to other hepatic disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice that had humanized livers. Injections of HCV-infected serum samples from patients were given to the mice, along with DAAs to eradicate the virus. Integrative pathway analyses were conducted to identify those pathways associated with the risk for HCC, which were then validated via analyses of paired HCC tissue from 8 patients with an SVR to DAA treatment of HCV infection.

Results of the study demonstrated that chronic HCV infection induced specific genome-wide alterations in H3K27ac antibodies, which were linked to changes in expression of proteins and mRNAs. These changes persisted after an SVR to DAAs or interferon-based treatments. According to integrative pathway analyses of liver tissue from patients and from mice with humanized livers, HCV-induced epigenetic modifications were shown to be associated with the risk for liver cancer.

Increased expression of the sphingosine kinase 1, SPHK1, oncogene was associated with a risk for HCC. The researchers validated these findings in an independent cohort of 216 patients with HCV-linked cirrhosis, of whom 21 achieved viral clearance.

The investigators concluded that the epigenetic and gene expression alterations that were identified might be targeted to prevent the development of liver cancer among patients who are treated for HCV infection. Epigenetic reprogramming appears to drive HCV liver cancer risk after DAA cure.

Reference

Hamdane N, Jühling F, Crouchet E, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response [published online March 2, 2019]. Gastroenterology. doi:10.1053/j.gastro.2019.02.038