Mono Virus Turns On Cancer Related Genes

September 11, 2020

A type of herpes virus, one that causes a single, can, in rare cases, raise the risk of developing certain types of cancer. Now researchers know how. the Epstein-Barr virus (EBV) can attach directly to bundles of genetic material in infected cells and “turn on” nearby genes, turning healthy cells into cancer cells, according to a new study of human cells.

Not all people infected with EBV develop cancer; but in rare cases, the virus can raise people’s risk of developing nasopharyngeal cancer, Burkitt’s lymphoma and certain stomach cancers, according to the American Cancer Society. While more than 90 percent of people worldwide are infected with the virus, only about 1.5 percent of cancer cases are linked to the infection, according to a 2019 report in the journal Annals of Pathology. Other viruses that drive cancer growth, such as hepatitis B and human papillomavirus (HPV), do so by worming their way into the genomes of their infected hosts – but researchers have just discovered that EBV takes a different approach.

Instead of intertwining with the host DNA, EBV DNA binds to the surface of the host DNA, causing the molecule to change shape and turn on nearby cancer-related genes, study author Patrick Tan, executive director of the Genome Institute of Singapore and a professor at the Duke National University School of Medicine, told Live Science in an email. The study, published in the July 27 issue of Nature Genetics, pinpoints exactly where the viral DNA grabs onto the host genome.

Understanding this process could allow scientists to develop drugs and gene therapies to undo harmful modifications to the virus, Rona Scott, an associate professor of microbiology and immunology at Louisiana State University Health Shreveport who was not involved in the study, told Live Science in an email.

In addition, “identifying footprints [or telltale markers] of EBV infection in cancer may help us determine whether EBV causes other cancers not yet associated with this virus,” she said.

Damaging cellular DNA
While some details remain murky, “the link between EBV and certain types of cancer has been known for years,” Tan said. For example, the virus has been linked to about 8 to 10 percent of stomach cancers, which together are the third leading cause of cancer deaths worldwide, according to a statement from the Duke Nurse School of Medicine.

Past research has explained one way EBV contributes to cancer. According to a 2007 report in the journal Cancer Science, the virus triggers a chemical reaction that labels molecules called methyl groups onto genes, turning them “on” or “off.” One theory is that these so-called epigenetic modifications, or modifications “on top of” the genome, disable genes that would normally inhibit tumor growth.

But Tan wondered if EBV was also altering the 3D structure of the host genome, thereby increasing the risk of cancer.

Cells pack DNA into organized bundles called “chromatin,” and some genes are hidden within the bundles beyond the reach of cellular machinery, which converts them into proteins. Thus, the structure of the chromatin determines which genes can be turned on or off, and when. While this is a useful control mechanism in healthy cells, according to a 2016 report in Science, certain changes in chromatin structure can spur cancer development – and Tan and his colleagues believe EBV may distort host chromatin in this way.

To find out, the team examined healthy stomach cells and cancerous stomach cells grown in culture, as well as cells sampled from patients with EBV-associated gastric cancer, to compare the structure of their genetic material.

They found that EBV DNA is also packaged into chromatin bundles that bind directly to specific points within the chromatin of infected gastric cells. That is, viral DNA attaches to regions of the host’s genome known as gene enhancers, which help activate specific genes. The authors found that while the gene enhancers were turned off in healthy cell samples, these enhancers were turned on during EBV infection and promoted the activation of cancer-related genes, particularly those that stimulate cell growth and proliferation. When dysregulated, these genes stimulate tumor growth.

“We were definitely very surprised by the results,” because we didn’t expect the viral genome to be directly involved in rewiring the host cell and controlling which proteins it builds, Tan said.

Even when the authors removed EBV from the infected cells, the structural changes the virus made to the host DNA remained. This finding supports previous evidence that EBV may contribute to cancer in a “hit and run” fashion, meaning that even if you eliminate the virus itself, the cell’s DNA is still altered and continues to drive tumor growth, Scott said.

But this theory must be confirmed in future studies, Tan added. The team also aims to investigate whether genes modified by this process could serve as new drug targets for EBV-related cancers, he said.

Perhaps other factors, such as a cell’s innate defense against the virus, determine which genes EBV can manipulate and in which people, though this too must be confirmed, Scott added.

In many EBV infections, the virus carries out its life cycle tucked away in immune cells called B cells and epithelial cells, which line the surface of the body, “without much consequence” to the health of the infected person, Scott noted. However, in cases where the virus does contribute to cancer, disrupting its ability to remodel host DNA may be a key avenue for treatment, she said.