Hi everyone! My name is Dong and I’m a PhD student under Thomas Tu. I’ve been working on understanding the consequences of HBV X protein (HBx) expression from HBV DNA integration, and its role in genomic instability.
More than 90% of HBV induced Hepatocellular Carcinomas (HCCs) contain multiple HBV integrations in contrast to 1 in 10,000 of the surrounding hepatocytes. This suggests a strong association between virus integration and HCC development, but we don’t know exactly how integrations cause cancer over decades of infection.
I’m interested in how HBx (the smallest HBV protein) is involved. It is usually really important for virus replication, but it can also affect DNA stability in the host cell.
When HBV DNA integrates into the host genome (as opposed to making cccDNA), bits of the virus DNA get chopped off. This means the integrated HBV cannot produce infectious virus and represent a replicative dead-end. It also means some bits of HBx are cut off, so it may not work or it works differently.
My job is to see if the HBx derived from integrations is functional and could contribute to cancer.
We have developed novel molecular tools to isolate, manipulate, and characterize cells containing HBV integrations. We generated over 100 cell clones with de novo integrations.
Under our model, we found integration junctions found that HBx regions required for DNA destabilisation were present in over 70% of integrations. We found that HBx expression from the integrations averaged ~4-fold lower than expression from cccDNA. We also found that at least some of the integrations were functional and that cells with existing integrations were 2-12 fold more susceptible to integrations after a new HBV infection (consistent with DNA instability).
Figure 1: HBV integration promoting a self-amplifying process through HBx expression
So now we’re developing a new model of understanding liver cancer: we think that genomic instability is driven by virus integrations and that this instability leads to more integrations, promoting a self-amplifying process (Figure 1). The resultant exponential increasing genomic instability then fuels accelerated acquisition of cancer driver mutations.
Hi@chigoziekingsley5454, thank you for the question.
Although it is difficult to clear integrations that are established early, preventing new infections (e.g., by reducing viral load or entry inhibition) at the appropriate points during chronic infection could limit new integrations. These therapies could also act to limit inflammation, preventing ongoing clonal expansion and amplification of existing integrations.
The emerging technologies like CRISPR(mutating HBx) and RNA interference (transcriptionally silencing of HBx) are being explored for specifically target HBV DNA integration. Studies have shown effects on HBx-dependent replication and to some extent DNA damage. However, it is still unclear whether these could induce a reduction of HBV-associated liver cancer, independent of their antiviral effects.
Thanks for the response sir, another question people who are inactive and always have there viral loads below 2000ul/ml, are they still at risk of developing liver cancer
Inactive carriers with low viral DNA levels are generally at lower risk of liver cancer compared to active carriers. However, the risk of liver cancer is not completely absent.
A long-term follow-up study has shown that a small percentage of inactive carriers can develop liver cancer over time; the inactive carriers of HBV (seronegative for HBeAg, serum levels of HBV DNA <10,000 copies/mL, and normal liver enzymes) had 5-fold greater risk for HCC than controls (HBsAg-negative) (Chen JD, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. 2010).
The risk of liver cancer in HBV infection is influenced by several known factors including viral load, age, family history of liver cancer and lifestyle. There are also potentially unknown factors, and research is ongoing to better understand them and develop strategies to reduce the risk. As I previously introduced my research, we suspect that integrations may play some role in promoting cancer.
Hi Dong, this is very interesting information and I thank you for researching and also explaining in a way that a lay person can attempt to understand. You mentioned that people with HBV whose viral load was below 10,000 copies still have a 5 fold greater risk of developing HCC than the controls. I was wondering if you have statistics for what those numbers are for the controls, that is what is the lifetime risk of developing HCC for someone who doesn’t have HCC? Thanks, Karin
.