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

Abstract

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 Gastroenterology 2019;156:2313-2329 BASIC AND TRANSLATIONAL LIVER with humanized livers. METHODS: We performed genomewide 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 ¼ 216), a subset of which (n ¼ 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.

Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China

“…Currently, no effective vaccine for HCV is available worldwide, which has greatly hampered the prevention of HCV infection and liver cancer due to hepatitis C. Although the treatment of HCV infection has progressed considerably as a result of the implementation of interferon‐free, direct‐acting antiviral (DAA)‐based combination therapies, the resistance of HCV to DAAs has played an important role in the failure of interferon‐free treatment regimens . Moreover, those fortunate enough to be cured of chronic hepatitis C with DAAs may remain at risk for liver cancer for an indefinite period . Consequently, the prevention of liver cancer due to hepatitis C should involve at least three aspects: (a) preventing widespread transmission of HCV among the general population, (b) continuously investing in the development of the HCV vaccine, and (c) strengthening programs for weight management and increasing the rate of antiviral treatment for HCV as these drugs become less expensive to procure.…”

“…37 Moreover, those fortunate enough to be cured of chronic hepatitis C with DAAs may remain at risk for liver cancer for an indefinite period. 38,39 Consequently, the prevention of liver cancer due to hepatitis C should involve at least three aspects: (a) preventing widespread transmission of HCV among the general population, (b) continuously investing in the development of the HCV vaccine, and (c) strengthening programs for weight management and increasing the rate of antiviral treatment for HCV as these drugs become less expensive to procure. Alcohol use and NASH are widely known risk factors for the development of liver cancer.…”

Interferon Is Superior to Direct Acting Antiviral Therapy in Tertiary Prevention of Early Recurrence of Hepatocellular Carcinoma

“…Recent studies showed the loss of intrahepatic immune activation by IFNα after DAA therapy due to the decreased levels of chemokine C-X-C motif ligand 10 (CXCL10), CXCL11, and a rapid decrease in NK cell activation and a normalization of NK cell cytotoxic effector functions [48], leading to ineffective surveillance of neoplastic clones. Another possible explanation is the epigenetic changes that induce H3K27ac modifications by chronic hepatitis C infection, associated with increased HCC risk, which persists even after HCV cure by DAA therapy [49].…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…These two genes are important in HCC development since the functional knockout of these two genes has been shown to inhibit HCC growth. 325 A recent publication supports the data showing that SOX gene signatures are associated with the expression of liver cancer dedifferentiation markers. 327 The development of an oncogenic signature relates to SOX expression.…”

“…Two studies have used chromatin immunoprecipitation and DNA sequence analysis from chronic HCV patients with or without DAAs treatment. 325,326 Hamdane et al showed that the expression levels of 2 genes: sphingosine kinase 1 and SOX-2, a transcription factor, did not change after HCV cure. The expression levels of these two genes were examined in the samples of patients before and after HCV cure as well as HCV-induced HCC samples.…”