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New Insights into Mechanism for Epstein-Barr Virus-Associated Stomach Cancer

Researchers from Chiba University, Duke-NUS Medical School and the Agency for Science, Technology and Research (A*STAR) uncover the mechanism behind the relationship between the Epstein-Barr virus and cancer development, including the involvement of epigenetics.

The Epstein-Barr virus (EBV) is typically known to be relatively harmless. Also known as human herpesvirus 4, EBV infections spread primarily through bodily fluids such as saliva. The condition often associated with it is infectious mononucleosis, also known as mono.

However, many individuals who have been infected with EBV may not even know that they were infected, since infection that occurs in childhood often presents with little to no symptoms. In children, any symptoms observed, such as fever, fatigue and sore throat, are usually similar to other common illnesses, therefore EBV infection is rarely diagnosed. In teenagers or adults, EBV infections are more likely to produce more serious symptoms, including swollen lymph nodes, enlarged spleen, and even Chronic Fatigue Syndrome.

The symptoms of EBV infection are caused by the initial lytic cycle of the virus – the first cycle of viral reproduction in which infected cells are destroyed. While individuals who have recovered from the symptoms develop adaptive immunity against EBV, the virus remains latent in one’s immune B cells or epithelial cells for the remainder of one’s lifespan.

Despite the relatively benign characteristics of EBV, it has been associated with increased risk of developing certain forms of cancer, such as nasopharyngeal cancers, Burkitt’s lymphoma, Hodgkin’s lymphoma, and gastric adenocarcinoma, which is also known as gastric or stomach cancer.

EBV has been linked with 8 to 10 percent of stomach cancers, which is considered to be a one of the most prevalent forms of cancer and is the third leading cause of cancer-related death worldwide. The Asia Pacific region is believed to have the world’s highest incidence rate of liver and stomach cancers.

A new study by researchers working together in Japan and in Singapore may have uncovered a mechanism linking EBV infection with the increased risk of stomach cancer.

The study was spearheaded by researchers from Chiba University in Japan, Duke-NUS Medical School, Singapore, and the Agency for Science, Technology and Research (A*STAR)’s Genome Institute of Singapore. Their findings were published in Nature Genetics in July this year.

The group of researchers conducted a thorough analysis of three-dimensional genomic structures in gastric cancer cell lines, gastric cancer patient samples, healthy gastric epithelial cells, and EBV-associated gastric cancer cells. Specifically, they looked at the epigenetic landscape and changes to the epigenome associated with EBV infection.

Epigenetics refers to the study of phenotypic changes that can be inherited, but that do not involve changes in the DNA sequence. Therefore, the epigenome is dynamic and can be altered in response to external stimuli. In cases of epigenetic changes being linked to increased cancer risk, external stimuli may be responsible for abnormal DNA modifications which alter gene expression and consequently result in cancer.

Investigations of the epigenome of human gastric cancer cells, combined with results from virus infection analyses, showed the presence of epigenetic changes on certain genomic regions, and that these changes were specific to EBV-positive stomach cancer. When cultured stomach cells were infected with EBV, the same epigenetic changes were observed.

According to Professor Atsushi Kaneda from the Graduate School of Medicine at China University, “Cells put active marks on genomic regions necessary for their behaviours and utilise them, and inactive marks on unnecessary genomic regions that are tightly closed and not to be utilised. We made the striking observation that strong inactive marks were lost in specific genomic regions when we infected stomach cells with EBV.” This means that in stomach cells infected with EBV, gene expression may have been upregulated at affected gene regions.

Besides increased gene expression, the researchers also observed that genetic enhancers that are typically “silenced” in closed genomic regions were activated in EBV-infected cells. These genetic enhancers promote gene expression, so cancer-related genes may be upregulated, without the genetic sequence itself having to be altered.

On the above findings, Professor Patrick Tan from the Programme in Cancer and Stem Cell Biology at Duke-NUS and the Singapore Gastric Cancer Consortium noted that “EBV DNA bound to largely the same genomic regions that also showed abnormal activation. These same regions also changed from inactive to active states by experimental EBV infection.”

The study also revealed that besides the genetic enhancers’ ability to activate cancer-causing genes and promote cancer development in various cell types, the epigenetic changes induced by EBV infection persist and remain stable even after traces of the virus are removed.

The discovery of mechanisms through which EBV infection may be related to increased cancer risks is not only applicable to the context of stomach cancer but may be relevant to other forms of cancer as well. The link between EBV, epigenetic modifications, and cancer is also an exciting one, as it provides new therapeutic targets and directions for future research in cancer development. [APBN]