New results suggest that bladder cancer could be caused by the body’s response to common childhood virus
Data published today in Science Advances, from Dr Simon Baker’s group at the University of York, suggests that BK virus can trigger changes in DNA that drive bladder cancer development, which kidney transplant recipients are at much greater risk of. The study was funded by Kidney Research UK and York Against Cancer.
The impact of BK virus on kidney transplant recipients
BK virus is a common virus that nearly everyone picks up in childhood generally without noticing. Once you have been infected with BK virus, it can hide in the kidneys without causing obvious symptoms. Reactivation of BK virus can happen in kidney transplant recipients due to their immunosuppressive medication. These drugs prevent the immune system from attacking the new kidney, but they also make it harder to fight off infections such as BK virus.
Reactivated BK virus infection can affect the kidneys, ureter (the tube connecting the kidney to the bladder) and bladder, potentially resulting in kidney damage. When kidney damage occurs, it is known as BK virus-associated nephropathy (BKVAN or BKN), which affects around 5% of transplant recipients.
Currently there are no specific treatments for BK virus or its complications. Reducing immunosuppressive medication helps the immune system to fight BK virus, but it carries the risk that the immune system might damage the transplanted kidney.
Kidney transplant recipients face a significantly higher risk of developing bladder and ureter cancers
We know that kidney transplant recipients develop ureter and bladder cancers much more frequently than the general population, linked to BK virus infection.
“Kidney transplant recipients are at over three times greater risk of bladder cancer. We have suspected that BK virus is involved in bladder cancer in transplant recipients, but little was known about the processes within the body that led to these cancers. Our results not only tell us more about how urinary tract tumours might develop in transplant recipients, but also suggest that BK virus may be involved in cancer development in the rest of the population.” Dr Simon Baker.
What is bladder cancer?
The urinary bladder is an organ that stores urine at low pressure to protect the kidneys. Bladder cancer refers to an abnormal growth of cells (tumour) that develops in the bladder lining (known as the “urothelium”). Each year in the UK there are over 23,000 new cases of bladder cancer.
Dr Simon Baker explains the research in this video
Uncovering the role of enzymes in bladder cancer development
Bladder cancer is caused by DNA damage (“mutations”), leading to changes in genes that can turn healthy cells into cancer. Most of the genomic changes found in bladder cancer cells are related to a group of enzymes called ‘APOBECS’.
APOBECS help the body fight viruses by damaging viral DNA. Bladder cancer is much more common in smokers, and scientists were expecting to see DNA damage caused by smoke exposure but were surprised to instead find APOBEC mutations. An additional complication that researchers had to explain is why bladder cancers do not normally contain detectable viruses when they are diagnosed. This study helps explain how bladder cancers might end up with so much DNA damage caused by a known antiviral response.
BK virus reactivation can trigger mutations that drive bladder cancer
In this study, Dr Simon Baker and the team at the University of York took cells from the urothelium and performed controlled exposures to BK virus, analysing the pattern of DNA damage caused by the viral infection over a period of weeks and months in the laboratory.
For the first time, they saw patterns of changes in the DNA of human cells that were very similar to the way that BK virus DNA is damaged as part of an antiviral response. This damage to host cell and viral DNA is caused by part of the cell’s antiviral weaponry known as “APOBEC” enzymes. Simon’s results provide evidence suggesting that BK virus infections drive an increased risk of bladder cancer in kidney transplant patients through the action of these DNA damaging APOBEC enzymes.
Simon added “In other types of virus-related cancer, such as cervical cancer, we know that virus DNA combines with our own genetic material to drive tumour development. Our results have shown that in the bladder, the tissue’s defensive response to the virus causes DNA changes which can lead to cancer. We found that DNA damage happens not only in infected cells but also in surrounding “bystander cells” witnessing infection in their neighbours. This DNA damage to uninfected cells could help explain why bladder cancers normally show no trace of viruses when they are diagnosed years later.”
David Crosby, chief research officer at Kidney Research UK commented: “These findings strongly suggest that we should be taking the management of BK virus seriously to support health of kidney transplant patients. We are delighted to be supporting Simon to undertake further research in this area which could lead to the development of new treatment options for at-risk patients.”
Patients at the heart of research
“My research is inspired by kidney transplant recipients. Kidney disease is a very difficult condition to live well with, and we want to ensure that when someone receives a donated kidney, they enjoy the best health possible, for as long as possible. My Kidney Research UK fellowship has allowed us to better understand how the BK virus may be driving bladder cancer so that we can find new treatments that will allow us to control this virus and reduce the risk of bladder cancer and BK virus-associated nephropathy in the future.
When I started my fellowship, I was surprised to find there was no widely available evidence-based patient information and that clinical practice in managing BK virus infections across the UK was very variable. I have been really pleased over the fellowship to have been involved in drafting a patient information leaflet and contributing to the first UK Guideline on BK virus management for the British Transplantation Society. These additional activities help my fundamental research to have more immediate impacts for patients.” Dr Simon Baker.
What impact does BK virus reactivation have on patients?
Tim Tavender had a kidney transplant in 2015, shortly afterwards his health deteriorated due to BK virus and, subsequently, bladder cancer.
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