Epigenetic changes persist after hepatitis C cure in liver cells, may predict liver cancer

Hepatitis C infection leaves permanent changes in the activity of genes in the liver even after the infection is cured and these changes are associated with an increased risk of liver cancer, French researchers have reported in the journal Gastroenterology.

The findings suggest that people with advanced liver disease may remain at higher risk of liver cancer after being cured of hepatitis C and will need long-term, regular screening for hepatocellular carcinoma (HCC; liver cancer).

The researchers say that their study provides the first evidence of epigenetic changes caused by hepatitis C virus (HCV) that are associated with HCC.

Epigenetics refers to the activity of chemicals and proteins which bind to DNA and influence when the genes made up by DNA are active and when they are silent. Epigenetic changes occur when cells alter the ways in which they turn on or turn off the activity of genes. Epigenetic changes can be triggered by external environmental factors including diet and toxins but also by disease processes in the human body.

At the molecular level, epigenetic changes take two forms. DNA may become methylated, or capped, by a methyl molecule group. This prevents expression of the DNA.

DNA is packaged to fit inside cells by wrapping around histones. When it is wrapped tightly it cannot be read, so its instructions cannot be used to make new proteins.

These epigenetic changes can be transient or permanent and govern how genes operate at a cellular level. For example, genes which code for production of bone may be present throughout the body but epigenetic factors will determine which cells use the gene instructions to make bone.

Researchers have been investigating the role of epigenetic factors in the development of various cancers, especially the ways in which epigenetic changes switch on the growth of cancer cells and how these epigenetic changes come about. Learning more about epigenetic changes that lead to cancer may help to predict who is at risk of specific cancers. Epigenetic changes are reversible, so it may be possible to design treatments that can block or reverse the epigenetic changes that lead to the growth of cancers.

French researchers have now reported that hepatitis C infection leads to permanent changes in histone structure in liver cells, altering gene expression. These changes are most pronounced in liver tissues of people with advanced fibrosis and cirrhosis and are associated with an increased risk of developing HCC. The changes remained detectable in people who had been cured of hepatitis C and were not detectable in people with hepatitis B or non-alcoholic steatohepatitis (NASH).

The research group looked at samples of liver tissue from six people without HCV, 18 people with chronic untreated HCV infection, eight people cured with direct-acting antiviral (DAA) therapy, 13 people cured with interferon-based therapy, four people with hepatitis B and eight people with NASH.

They found that in people cured of hepatitis C, specific epigenetic modifications persisted, regardless of whether they had been treated with DAAs or interferon-based treatment.

Furthermore, they found that epigenetic changes were more likely to persist after cure in people with advanced (F4) fibrosis. These epigenetic changes were associated with greater expression of oncogenes associated with tumour size and progression in HCC and lower expression of a potential tumour suppressor gene in the liver.

The researchers also found that about 900 genes with epigenetic modifications are linked to carcinogenesis.

“HCC is often asymptomatic and thus remains undiagnosed until late stage. Therefore, there is an urgent medical need for biomarkers to predict HCC risk,” the researchers conclude. ”Showing that HCV induces persistent epigenetic alterations following DAA cure provides a unique opportunity to uncover novel biomarkers for HCC risk. Furthermore, by uncovering virus-induced epigenetic changes as therapeutic targets, our findings offer novel perspectives for HCC prevention – a key unmet medical need.”