Epstein-Barr Virus Linked With Gastric Cancer

A substantial proportion of gastric cancers worldwide were linked with the Epstein-Barr virus (EBV), according to a meta-analysis.

In a pooled analysis involving over 68,000 patients with conventional gastric adenocarcinoma in 37 countries, EBV prevalence in tumor cells was 7.5%, and was similar across regions, reported Catherine de Martel, MD, PhD, of the International Agency for Research on Cancer in Lyon, France, and colleagues writing in Clinical Gastroenterology and Hepatology.

If there were a causal relationship, some 81,000 conventional gastric adenocarcinoma cases (71,000 men and 10,000 women) would be potentially attributable to EBV worldwide, “in addition to 150,000 cases of other cancers causally associated with EBV such as nasopharyngeal cancer, non-Hodgkin lymphoma, and Burkitt lymphoma,” the researchers noted.

Growing evidence points to an etiological role of the ubiquitous gamma herpesvirus, which often leads to mononucleosis, in gastric cancer as well. As the fourth most common and deadly cancer worldwide, gastric cancer accounted for more than one million new cases and 770,000 deaths in 2020 worldwide, de Martel’s group noted.

“Development of an EBV vaccine may be the key to EBV-associated cancer prevention,” they suggested.

One potential mechanism is that EBV may increase the risk of malignant transformation in the stomach through gene expression regulating microRNAs, such as BARF1, “which are strongly expressed in gastric cancer cells and have been shown to act as oncogenes, promoting cell proliferation by up-regulating transcription factor signals and reducing cell cycle inhibitors,” the researchers noted. Also, EBV latent membrane protein 2A (LMP2A), often expressed in EBV-associated gastric cancer, induces DNA methylation, they pointed out.

For this study, de Martel and colleagues pooled data from 220 studies on 68,908 patients with conventional gastric adenocarcinoma from Jan. 1, 1990, through Aug. 31, 2021, across 37 countries. Over half of the studies came from eastern Asia, followed by 44 from Europe, 21 from South America, and 16 from North America, among others. Studies included had at least 20 gastric adenocarcinoma cancer patients assessed for EBV using in-situ hybridization.

EBV was even more common in patients with lymphoepithelioma-like gastric carcinoma (LELC, 75.9%) and remnant or stump adenocarcinoma (26.3%). “Lymphocyte attraction in a post-surgery damaged gastric epithelium could also explain the high number of EBV-positive stump/remnant adenocarcinomas found in this review,” the group wrote.

Factors tied to a higher prevalence of EBV among gastric adenocarcinomas worldwide included:

• Proximal region tumor location: prevalence ratio [PR] 2.5 (95% CI 2.0-3.1)
• Male sex: PR 2.1 (95% CI 1.9-2.3)
• Diffuse-type tumor: PR 1.3 (95% CI 1.1-1.5)

No difference in EBV prevalence was observed by gastric cancer stage.

Since higher EBV prevalence occurred among men, researchers suggested estrogen may have a protective role in EBV-associated gastric cancer. “Another hypothesis is that biallelic expression of tumor suppressor genes on the X chromosomes better protects women against EBV carcinogenesis,” they wrote.

The authors acknowledged limitations to the data. Not all studies specified whether the subtype LELC was included. Moreover, while most included studies were from eastern Asia, only a few were from Oceania or sub-Saharan Africa. Additionally, heterogeneity was high among studies and data about important potential confounders, such as age and smoking, were limited.