Viruses are very much in the frame at present, with the Coronavirus causing havoc in China, and disruption across the world. Viruses, epidemics and vaccination are an interesting topic that I will present on another occasion. But can a virus cause cancer in humans? There has been research over nearly a hundred years showing certain [...]


Can a virus cause cancer?


Viruses are very much in the frame at present, with the Coronavirus causing havoc in China, and disruption across the world. Viruses, epidemics and vaccination are an interesting topic that I will present on another occasion. But can a virus cause cancer in humans? There has been research over nearly a hundred years showing certain viruses could cause cancer in small laboratory animals.

Dennis Burkitt, an Irish surgeon who served in Kenya and Africa during and after the Second World War made many important discoveries and associations that have influenced generations of doctors. He was a deeply committed Christian, and felt his calling was to serve in Africa. During the middle of the 1950’s he began to notice a common and distinct group of children with aggressive malignant jaw tumours, who also developed secondary tumours elsewhere in their bodies. He kept copious notes, and studied these children in detail.

When he eventually qualified for long service leave he spent it driving around central Africa in an old Land Rover documenting the distribution of these tumours. He made the startling discovery that these tumours largely occurred in areas in Central Africa above a certain elevation, where Malaria was hyper endemic.

He published these findings in 1957, and not surprisingly he thought that this might be a disease transmissible from mosquitos. In 1961 he gave a lecture in London ‘The Commonest Children’s  Cancer in Tropical Africa—A Hitherto Unrecognised Syndrome’ which was attended amongst others by Dr Daniel Epstein, who approached him after the talk, saying that he thought there was a good chance that this cancer was associated with a virus. Epstein was an expert electron microscopist, a new technology at the time, and he convinced Burkitt to send him some samples. Epstein was proved right, and the Epstein Barr virus (EBV) was discovered within tumourcells, and the research published in 1964.

The jaw tumour is now called “Burkitt’s Lymphoma” and it occurs in an endemic form in tropical Africa, Papua New Guinea and South America, and where malaria is common. The sporadic form occurs elsewhere. The tumours can be cured with chemotherapy in up to 90% of cases.

We now know that EBV is acquired by most children through the oral route and 90-95% of adults worldwide show exposure to EBV.When acquired later as adolescents it can produce the syndrome “Infectious Mono-Nucleosis” or Kissing Disease, a painful but usually self-limiting disease. So the great majority of us exposed to EBV do not get cancer. So how can we “know” that EBV causes cancer?

In an article last month in ST I described “Koch’s Postulates”, which allows us to work out whether a given bacterium does cause a disease. This approach can hardly work for a virus; for a start everyone has  evidence of EBV infection. Not many of us thankfully have cancer. Also there will be ethical difficulties in giving volunteers a virus to see if they get cancer. Viruses have to be grown on cells and it would be impossible to transfer a “pure” virus.

It turns out that EBV is taken up by the immunological cells, B and T cells. In the B cell particularly it inhibits the innate mechanisms within the cell which cause it to die (apoptosis) resulting in long term infection. Small parts of the virus’s genetic material, the genome, are made available to these cells and can become incorporated into the genes of the host cell. The molecular basis of cancer, which consists of the uncontrolled proliferation of cells, is complicated and incompletely understood; but there are some genes which promote cancer, (oncogenes, proto-oncogenes and those that supress cancer.

In EBV infection and Burkitt’s Lymphoma for instance, we see a translocation from chromosome( the long strings containing the genes) number 8 to chromosome 14, which now places an oncogene in line next to a gene which produces immune cells, B cells, and may result if not supressed, in their uncontrolled proliferation to  B cell lymphoma; like Burkitt’s. But there are other manifestations of this, as Hodgkin’s and non-Hodgkin’s Lymphoma and T cell Lymphoma.

We recognise that EBV is also taken up by cells in the lining of the upper airway and may produce nasopharyngeal cancer, which is common in some countries. All these cancers become much more common where an individual’s immunity is supressed. This often occurs after chemotherapy for cancer, long term immuno-suppressants for inflammatory disease, and in infection with the Human Immunodeficiency Virus, HIV.

We think that EBV contributes to 1.5% of all cancers. But it is likely that up to 15% of all cancers are associated with viruses and express virus genes. While this is a problem, it immediately suggests solutions. Immunisation is one of them.

Cervical Cancer causes 8% of all cancer associated deaths. It is particularly common in the developing world, where death rates are the highest. In the West active screening programmes, the Pap test, assists early diagnosis and treatment, so that advanced disease is uncommon. 90% of all cervical cancers are caused by The Human Papilloma Virus (HPV). Fine work done in Australia by Professor Ian Frazer led to the introduction of a vaccine, Gardasil in 2007. The original vaccine had activity against 4 serotypes, responsible for 70% of the cancers. A new vaccine Gardasil9, active against 90% of strains, has just been released, available free to all girls and boys. Boys of course can harbour and transmit these infections.

HPV is also the cause of a majority of anal and oro-pharyngeal cancers, and also genital warts, and the connection would be obvious to most readers. The population based introduction of this vaccine may well eradicate HPV infections in Australia, a thoroughly remarkable achievement. The cost of Gardasil has prevented worldwide uptake of this vaccine, but hopefully this could be resolved.

When I was training in surgery in England in the 1980’s, one of my colleagues pricked his finger with a needle while stitching. He contracted the highly contagious Hepatitis B virus (it was called Australia Antigen then, having been identified in indigenous Australians in 1966) and died from liver failure a few weeks later. Hepatitis B is endemic in many parts of the world, and has been around for millennia. In Africa and the Middle East the population prevalence is 15%. In Asia slightly less at 10%, and in Europe about 1%. It is acquired at birth in endemic areas, and these children usually become chronic carriers of the disease, and are at risk of getting liver cirrhosis, and liver cancer.

When the disease is picked up later or in adulthood, through intravenous drug use, transfusion, or sex, an acute hepatitis may occur, but the virus may be cleared. Antibodies to the Australia Antigen (HB surface antigen, HBs antigen), usually persist and are markers of immunity(surgeons should have regular tests for all these infectious viruses). A third of the population of the planet has evidence of previous contact with HBV.

Liver cancer, as a result, is one of the commonest cancers worldwide. The five-year survival is less than 20%, so it is one of the commonest causes of death from cancer worldwide. HBV probaby causes cancer in the liver in many ways. One mechanism seems to be by impairing the control of gene expression (methylation, acetylation for medical students) in the nucleus of liver cells. This results in genomic instability, faulty repair of DNA sequences, and an inhibition of apoptosis.

Vaccination for HBV became available in 1981, but was controversial as it was derived from the sera of gay men and intravenous drug users. This was developed in the 70’s before the appearance of the HIV virus, and some blamed this vaccine for the AIDS epidemic. This theory is now thoroughly discounted. The vaccine was replaced by the first recombinant vaccine derived from yeast that became available in 1986. Others have followed. These new vaccines are highly effective in preventing HB virus infection, and are part of National Health programmes worldwide.

The other liver virus, Hepatitis C is caused most commonly by intravenous drug use, and probably through sexual contact. It is commonest wherever drug use is common particularly in the West, the prevalence in these populations is about 2%. Its progress has similarities to HBV and it is responsible for liver cirrhosis and liver cancer as is HBV.

On the basis of good evidence, some cancers we think are associated with viral infections. But this may be misleading. This should be rephrased as “the origins of cancer are multifactorial. It depends on our genetic inheritance, toxins (cigarettes, alcohol, UV light exposure, chronic inflammation) and indeed viruses. These may be clear-cut as in Burkitt ’s lymphoma and Cervical Cancer, where a single virus is associated with disease. But it is highly likely that fragments of multiple viruses are incorporated into tissues to produce cancer. We “are” what we receive from our parents, our carers, our sexual partners, our occupations and our injuries. Our infections are an important part of this.

It is not all bad news. All these viruses associated with cancer, have signatures which are increasingly discoverable by the ingenuity of our researchers.

For instance a biopsy of a tumour will give us an idea of its genetic makeup, including its viral genes. Antibodies to these proteins can be made up and tagged with radiation sources. The patient can then be imaged to see where in the body the tumours are. Finally the anti-tumour antibody can be combined with a chemotherapy agent, or radiation source (theranostics). This is precision and personalised medicine. Brave New World!

(The writer is Associate Professor of Surgery at James Cook University, Cairns, Queensland, Australia)


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