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Genes controlling immune response to common viruses may influence glioma risk

New UCSF Brain Tumor Center study shows genetic link between Epstein-Barr virus and decreased glioma risk

Scientists know some viral infections can cause cancer later in life. Now, researchers at the UCSF Brain Tumor Center have identified a link between the genetic risk factors for glioma and the immune response to certain common viruses.

Their results, recently published in the American Journal of Human Genetics, suggest that variants in the genes that regulate the immune system are relevant for glioma.

“This work is getting at the fundamental question of how common viruses can potentially alter your risk for cancer,” said Stephen Francis, PhD, an associate professor in the department of neurological surgery and the senior author of the study.

Stephen Francis, PhD
UCSF epidemiologist Stephen Francis, PhD.

Single nucleotide polymorphisms (SNPs) are changes in the genome at a single position on the DNA. These small genetic variations are one reason that people react differently to the same infection. Several viruses people commonly encounter in their lifetime, like the Epstein-Barr virus, also stay in the body long after the initial exposure. These viruses transition from that lytic, infection-causing phase to a latent, inactive phase — and sometimes back again.

Scientists think that this complex interaction between a person’s genome and the complex dynamics of the viral exposure might also influence their risk for cancer.

Researchers who study the human genome often correlate SNPs with the risk for disease in a large population. A previous study identified SNPs associated with significantly different antibody responses to multiple viral antigens. The Francis lab then used these SNPs to generate what they called a genetic reactivity score — a measure of the inherited genetic programming that influences antibody response to viral antigens in three large glioma datasets.

“For these viruses where multiple independent SNPs all somehow affect how an individual reacts to that viral challenge, combining them creates more information than just looking at single SNPs,” said Geno Guerra, PhD, a postdoctoral scholar in the department of neurological surgery and the lead author on the study.

These scores were a tool that helped the researchers run more targeted genomic analyses investigating the connection between glioma and viral infections.

The scientists found that increased reactivity to a specific Epstein-Barr virus antigen called Zebra was related to a decreased risk for glioma. This antigen controls how the virus switches from the latent to the lytic phase of infection. Additionally, high reactivity to a different Epstein-Barr virus antigen called EBNA was associated with better glioma survival outcomes while high reactivity to a Merkel cell polyomavirus antigen correlated with an increased risk for glioma.

“This really gets at the complex immunologic architecture of both the virus and our genome," Francis said. "This is the result of an evolutionary arms race between viruses and our immune system.”

Epstein-Barr virus virions invading cells
Electron microscopy image showing Epstein-Barr virus virions

Many of the SNPs the Francis group identified as being correlated with glioma risk are on the human leukocyte antigen (HLA) genes. The scientists were able to further determine one HLA alle, or specific version of the DNA sequence at one location on the gene, was associated with both the immune response to Epstein-Barr virus Zebra and glioma risk.

The finding suggests the connection between Epstein-Barr virus Zebra antigen and glioma risk might be due to a shared biological phenomenon these SNPs contribute to, Guerra said.

But the HLA region has the most SNPs of any area in the human genome. Future studies in the Francis lab are focusing on more targeted, deep sequencing of the HLA genes to find out which SNPs influence the immune response.

This research lays the groundwork for future experiments to test how the immune system might be regulating both the response to viruses and with different HLA alleles.

Francis said this study also indicates the potential for anti-cancer therapeutics that target viral proteins.

The study indicates that this methodology to study the genetics underlying other cancers and diseases can help scientists figure out what it means for people and viruses to co-exist.