What is it about?

It is well established that infectious agents, such as bacteria and viruses, are involved in the development of a variety of human cancers and it is estimated that infectious agents are involved in 20-40% of cancers. Therefore, by finding out more about which infectious agents are involved and the effect they have could lead to a transformation in the outcomes of cancer patients. For the first time an international team, including researchers for the University of East Anglia, have performed a comprehensive study of which viruses are found in the cells of a large variety of cancers.

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Why is it important?

The involvement of viruses in the development of cervical, liver, and nasopharyngeal cancer are well established. Similarly, infection with bacteria, such as Helicobacter pylori infection, have been associated with cancers including those in the stomach, bladder and cervix. The HPV virus is understood to cause the majority of cases of cervical cancer (98%) and it is the most common viral infection of the reproductive organs. HPV implants DNA into the genome of human cells and causes these cells to become cancerous through stopping faulty cells killing themselves and encouraging the cells to replicate to become a tumour. A vaccine has been developed that prevents infection by the two most common types of HPV, HPV16 and HPV18, and this is now given routinely to young adolescent girls. In the UK it has been offered to all girls aged 13 years since 2008 and has reduced pre-cancerous cervical disease in women by 71% and is likely to prevent most cases of cervical cancer. Identifying new links between infection and cancer types has the potential to provide vaccines, such as the HPV vaccine, which could reduce the global impact of cancer.

Perspectives

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Project (PCAWG), is a collaboration involving more than 1,300 scientists and clinicians from 37 countries, that analyzed more than 2,600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was then the launch-point for 16 working groups studying multiple aspects of cancer’s development, causation, progression and classification. Previous studies focused on the 1 per cent of the genome that codes for proteins, while PCAWG explored in considerably greater detail the remaining 99 per cent of the genome and more. When a tissue sample from a cancer patient is sequenced, such as those in PCAWG, both human cells and any infectious agents present will be read. This has allowed an international team to systematically investigated the viruses found within the PCAWG dataset and examine the association with cancer characteristics. We discovered traces of 23 different virus types in 356 cancer patients, with 13 per cent of the samples having evidence of the presence of viruses. When analysing the whole cancer genome, we discovered traces of viruses in considerably more tumours than in earlier studies that were based on investigating the RNA only. Nevertheless, we were not able to confirm the common speculation that other, as yet unknown viruses are associated with cancer. As expected, the known viral drivers of tumour initiation and growth were the most common. The genome of Epstein-Barr viruses (EBV), which are known to cause a number of different types of cancer (particularly lymphoma, stomach cancer and nasopharyngeal cancer), was found in 5.5 percent of the cancer genomes investigated. Hepatitis B virus (HBV) DNA was found in 62 of the 330 cases of liver cancer. We found human papillomaviruses, most commonly HPV16, in 19 of 20 cervical cancers cases and in 18 of 57 head and neck tumours. We also ruled out a connection between some viruses, including adenoviruses and baculoviruses, and cancer. We also further identified some of the mechanisms that viruses use to trigger changes in the DNA of cancer cells. In some of the tumours linked to HPV and EBV, the characteristic changes in the DNA that drive cancer growth were missing. The presence of the virus presumably supports malignant characteristics. We also found that the presence of a virus in a tumour is associated with a pattern of changes in the genome that has been associated with faulty DNA damage repair mechanisms in the human cell. This suggests a role of impaired antiviral defence as a driving force in cervical, bladder and head-and-neck carcinoma. Viruses appear to be associated with much greater genomic instability i.e. sections are more likely to be duplicated or deleted than those without and high levels of one virus was associated with a worse outcome in kidney cancer. This is the first time that a systematic study of the majority of cancer types for viruses has been made. It is important as unveiling new links between infection and cancer types has the potential to provide actionable opportunities, for example HPV vaccines, which could reduce the global impact of cancer.

Professor Daniel S. Brewer
University of East Anglia

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This page is a summary of: The landscape of viral associations in human cancers, Nature Genetics, February 2020, Springer Science + Business Media, DOI: 10.1038/s41588-019-0558-9.
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