The eye cancer, called ocular surface squamous neoplasia, can affect people anywhere in the world but is between the fourth- and sixth-most-common cancer in sub-Saharan Africa, said Peter Angeletti, an associate professor of biological sciences at UNL.

Ultraviolet light is known to be a contributing factor to the cancer, which occurs in the top layer of cells in the eye, Angeletti said. So is HIV, which contributes to the high rates of the cancer in sub-Saharan Africa, where HIV rates also are high.

But researchers didn’t know the likely cause of the cancer, also known as OSSN, Angeletti said. Previous research wasn’t clear.

Angeletti applied for and received a grant from the National Institutes of Health to study the cancer. The researchers hypothesized that a virus was the cause, and they had a list of likely suspects.

Angeletti put his money on the human papillomavirus, or HPV, which causes cervical cancer and a handful of other malignancies in women and men. HPV is his main focus of study.

But samples from biopsies collected from 243 patients with the cancer who visited the University Teaching Hospital in Lusaka, Zambia, told a different story.

The researchers found little sign of HPV and lots of evidence of Epstein-Barr virus. The team, which includes collaborators in Zambia and elsewhere in the United States, published the study recently in the journal Frontiers in Oncology.

“This is the clearest evidence that has ever been seen that points to EBV as being very strongly associated with this cancer,” said Angeletti, who also is a member of the Nebraska Center for Virology.

Specifically, the researchers tested for six different viruses, including HPV and Epstein-Barr, looking for the viruses’ DNA, using PCR analysis. They also looked for proteins produced by Epstein-Barr, HPV and another virus called Merkel cell polyomavirus.

Only 9% of samples were positive for HPV’s genetic material and about 12% for that of the polyomavirus. Compare that with the 80% positive result for Epstein-Barr DNA. In addition, 89% of the samples were positive for the protein produced by Epstein-Barr.

“It looks very clear that EBV is likely to be the primary cause,” Angeletti said. “You can’t really exclude the possibility that there are other things. ... But the point is, EBV is likely to be the primary cause.”

The lead author of the study was Peter Julius of the University of Zambia School of Medicine, who spent time training at UNL. Also participating locally were researchers with the University of Nebraska Medical Center’s biostatistics department.

Nearly 73% of the patients in the study had HIV. But Angeletti said Epstein-Barr is likely to be the cause of the cancer not just in people who have HIV but also in those who don’t.

Working with a group that has a greater prevalence of the cancer made it easier to conduct the study, he said. People with HIV have a 12-fold increased risk of the eye cancer. They also are more likely to have other infections.

But the cancer also occurs elsewhere around the world, particularly in developing nations, he said. It’s seen occasionally in the United States, too, but broader access to good medical care means it’s less likely to result in long-term complications.

As scientists, Angeletti said, the researchers want to know what’s causing diseases so they can find ways to prevent them anywhere in the world.

About 90% of people become infected by Epstein-Barr by early adulthood. Most such infections are harmless. The virus doesn’t go away but remains in a latent state in the body.

Angeletti said antiviral drugs might prevent future troubles from the virus. Vaccines could be developed against it. A highly effective vaccine has been available for HPV for nearly 20 years.

The NIH announced last week that it is launching an early stage clinical trial to evaluate an investigational vaccine to prevent Epstein-Barr. The virus causes an estimated 125,000 cases of infectious mononucleosis a year in the United States; roughly 10% of those patients develop fatigue lasting six months or longer.

Moderna, maker of a COVID-19 vaccine, also is working to develop Epstein-Barr vaccines.

The virus already is known to cause several other kinds of cancer. It also has been linked in recent, unrelated studies to multiple sclerosis, an autoimmune disease.

Angeletti said an estimated 15% of human cancers are caused by viruses, and undoubtedly more have yet to be discovered.

“There are other reasons it’s smart for us to start to think about strategies to reduce the amount of infections,” Angeletti said, adding that the pandemic has taught everyone to take such infections seriously.

Angeletti said the team’s study may be different from past studies that did not find such a strong link to a potential cause for the cancer because the researchers have very sensitive techniques for detecting the virus and the proteins they produce.

“We think this is a game-changer,” he said.