Skin cancer is typically caused by damage to the skin's cells from ultraviolet radiation. But a recent case study has just shed light on another potential cause: human papillomavirus.
Author
- Sarah Allinson
Professor, Department of Biomedical and Life Sciences, Lancaster University
The report, which was published in the New England Journal of Medicine, focused on the case of a 34-year-old woman who had been diagnosed with over 40 squamous cell carcinomas (SCC). This is the second most common type of skin cancer.
The woman also had many wart-like growths in her mouth and on her skin. These were attributed to a human papillomavirus (HPV) infection.
Human papillomavirus is a common group of viruses that can infect skin and other parts of the body. While HPV often does not cause any problems or symptoms in most people, in some cases it can cause warts and is even linked to certain types of cancer - such as cervical cancer.
The woman in the latest report was referred by her doctor to the team of researchers who conducted the case study. She had already undergone multiple surgeries and rounds of immunotherapy to remove a large squamous cell carcinoma that repeatedly grew back on her forehead. The patient's doctor believed this might be due to a condition that made it more difficult for her immune cells to fight off the tumours.
The researchers performed a genetic analysis on this recurrent tumour to understand why it continued to grow back. Under normal circumstances, SCC tumours have a genetic signature that shows their mutations were caused by ultraviolet radiation. These mutations usually drive their growth.
However, this patient's cancer didn't have these signature mutations. Instead, the researchers found that the HPV infection living on her skin had integrated itself into the DNA of the tumour on her forehead. It seemed that it was the virus that was actually driving the cancerous growth.
There are more than 200 different types of HPV viruses, only a few of which have been associated with cancers . HPV19, which infects skin, had not previously been linked to cancer. But in this case, it had gone rogue and caused the carcinoma.
Unique case
This recent case study is unique, it should be said. There were many factors that made it possible for the HPV infection to drive the recurrent growth of skin cancer.
The patient had a long history of health problems beginning in early childhood. This had brought her to the attention of researchers who were studying people who had problems with their immune system. A 2017 case report on her revealed that she had inherited mutations in two genes that play a role in immune function.
One of the mutated genes was ZAP70, which is involved in the normal function of a type of immune cell called a T-cell. This cell plays an essential role in helping the body successfully fight infections.
Inherited changes in ZAP70 that prevent it from working were previously known to cause a condition called severe combined immunodeficiency . This condition is usually diagnosed in infancy and, if not treated with a stem cell transplant, leads to death within the first couple of years of life. Being in her late 20s at that time, the woman became the oldest patient ever to be diagnosed with a ZAP70 immune condition.
The second mutated gene, RNF168 , is involved in repairing damage to DNA.
The new team decided to investigate whether it was the unique combination of mutations in both genes that was allowing the HPV infection to cause cancer. However they concluded that the mutated RNF168 gene was a red herring.
The research team found that the patient's RNF168 mutation was relatively common in the wider American population and wasn't linked to any health issues. Further investigation of her cells also revealed that her DNA repair processes were functioning normally.
They then moved on to the ZAP70 gene. Here they found that although the patient's ZAP70 gene was mutated, it still partly worked. This explained why she hadn't succumbed to severe combined immunodeficiency in childhood. However, the mutation still made her immune system less effective. So because her T-cell response wasn't fully functional, her body was unable to recognise and eliminate HPV-infected cells.
After receiving a stem cell transplant that replaced her immune cells with fully functioning ones from a donor, the woman made a complete recovery. The new T-cells were able to recognise and destroy the HPV-infected cells, including the skin cancer. Hopefully she will now remain cancer-free for years to come.
Immune health and cancer
This story highlights how important our immune system is in protecting us against cancer. Without it, even innocuous viruses that usually harmlessly co-exist on our skin can drive the formation of aggressive cancers.
It also demonstrates how modern genomic technology is transforming our understanding of disease. Without genetic sequencing, doctors would still be none the wiser about why this unfortunate woman had so many aggressive skin tumours.
But this study also raises questions about whether HPV-driven skin cancer could be a wider, previously unrecognised problem. The authors suggest that in the future, patients with aggressive and recurrent squamous cell carcinomas should be profiled for T-cell function and the presence of HPV infections. Like the woman in this story, they too might benefit from immune boosting therapies to treat their cancers.
Sarah Allinson does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.
