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.
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
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
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.”