Viruses are more prevalent than once thought, with a significant role in development of humanity. A recent consensus approach based on whole genome and whole transcriptome sequencing reveals which human cancers are caused by viral infections.
There are an estimated 10 nonillion (1031) individual viruses on Earth. They are found everywhere and are known to infect all lifeforms. However, only a small subset is known to infect humans. These infectious viruses are microscopic parasites that replicate inside our living cells causing various diseases, including cancers.
During an infection, the virus will enter a host cell, then shed its coat to release its genes, taking over the cells biological machinery to reproduce and infect more cells. Interestingly, some viral genes can be integrated permanently, ultimately becoming part of the host’s genome. This means that the viral genes can be passed down from parent to child as part of the human genome (this is exceedingly rare, as most viruses infect only somatic cells and not the germline).
The presence of viral DNA in the human genome was recognized for a long time. However, full analysis was not possible until recently. The ability to study viral genes has provided insight into how these infectious agents are linked and contribute to the development of various human cancers. One example is the Human Papillomavirus (HPV), which is very strongly associated with cervical cancer, and head and neck cancers. HPV can cause cancer through infection of epithelial cells of our skin, or the mucosal cells in the inner lining of tissues (see figure below). Although most HPV infections are asymptomatic, the virus can persist in high-risk infections after integrating its genes into human DNA, ultimately contributing to the onset of cancer. Virus-induced cancers such as cervical cancer (from HPV infections) are considered deadlier than non-viral spontaneous cancers. HPV produces aggressive types of cancers because some of its genes are oncoproteins, i.e., proteins that disrupt tumor suppressors (the genes that protect us from cancers) and induce proliferation of cervical carcinoma cells.
The Human Papillomavirus (HPV) is a viral infection that can spread between people through skin-to-skin contact, usually during sexual activity. HPV infects the skin or mucosal cells which are cells lining the inside of the body. Most HPV infections are asymptomatic, often displaying no symptoms and will not cause problems. However, the persistence of HPV infection will result in high-risk infections where HPV will integrate into human DNA leading to development of cancer.
The ability of viruses such as HPV to alter human DNA along with their association with human cancers have increased the importance for genetic analysis. A worldwide study by Zapatka et al. (2020) conducts comprehensive genome and whole transcriptome analyses of various tissue samples from cancer patients. The work, which is a part of the Pan-Cancer Analysis of Whole Genome project (PCAWG), looks at tumor-associated viruses by aligning viral sequences against whole-genome and whole-transcriptome sequencing data from human tumors. The project has allowed for the characterization of numerous viral associations across 38 distinct cancer types, where some cancers are strongly associated with viruses while others are not (see figure below).
The study indicates that the top five most common virus genera are lymphocryptovirus, orthohepadnavirus, roseolovirus, alphapapillomavirus and cytomegalovirus, accounting for 85% of the viruses detected in the tumor samples.
Heat map indicating the total number of viruses detected for several cancer types. It shows the total number of genus hits (types of viruses) among tumor. Blue stands for Whole Genome Sequencing (WGS), light green for RNA sequencing (RNA-seq), and dark green for WGS and RNA sequencing. The top of the figure shows the fraction of virus-positive tumor samples (%) and the corresponding tissue type in the experiment. The second part of the figure indicates the type of non-malignant tissue in the study. The study indicates that 23 virus genera are detected among 356 patients with cancer. It shows the distribution of viral associations in human cancers, where some cancers like cervical cancer are almost always associated with viruses, while other cancers are not associated with viruses.
It is well established that infections from three of the five most prevalent virus genera can lead to tumor development. These include lymphocryptovirus (e.g., the Epstein-Barr virus or EBV), orthohepadnavirus (e.g., the hepatitis B virus or HBV), and alphapapillomavirus (e.g., HPV). To give an example, HPV was mainly detected in head and neck cancers, and cervical cancer samples which is already confirmed through existing scientific literature. In addition to detection of well-known virus-associated cancers, the study can also identify new viral species. Novel DNA segments were detected, however they are difficult to analyze. This is because these sequences are low in numbers and spread across various cancer types in contrast to sequences from well known viruses. Despite the low detection and wide distribution in cancer types, the presence of novel sequences indicates the ability of whole-genome sequencing and RNA-seq analyses to detect potentially new viral species and study their associations and effects in human cancers.
Overall, this study provides insight regarding the impact of viruses on human cancers and diseases at the genetic level. The ability to detect viral integrations may allow for the development of potential solutions that may prevent viral infections, and subsequent DNA integration and replication processes.
Learn more about cancer-associated viruses
- Viruses that can lead to cancer (American Cancer Society)
- What to know about viruses (Medical News Today)
About the Author:
This post was written by Peter Costa. He is looking forward to graduation of undergraduate program. He is excited to begin a new journey as future graduate student at U of T! Hoping for quick end of pandemic, he is eager to travel and explore more of Canadian coastal regions. In the meantime, he works to perfect his cooking, one burnt dish at a time.
The Genomic Odyssey 
Great explanations of the concepts Peter! I learned a lot.
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