Epstein–Barr Virus Infection and Gastric Cancer

Epstein–Barr virus (EBV) infection is found in a subset of gastric cancers. Previous reviews have exclusively focused on EBVencoded small RNA (EBER) positivity in gastric cancer tissues, but a comprehensive evaluation of other type of studies is lacking. We searched the PubMed database up to September, 2014, and performed a systematic review. We considered studies comparing EBV nucleic acids positivity in gastric cancer tissue with positivity in either adjacent non-tumor tissue of cancer patients or non-tumor mucosa from healthy individuals, patients with benign gastric diseases, or deceased individuals. We also considered studies comparing EBV antibodies in serum from cancer patients and healthy controls. Selection of potentially eligible studies and data extraction were performed by 2 independent reviewers. Due to the heterogeneity of studies, we did not perform formal meta-analysis. Forty-seven studies (8069 cases and 1840 controls) were identified. EBER positivity determined by in situ hybridization (ISH) was significantly higher in cancer tissues (range 5.0%–17.9%) than in adjacent mucosa from the same patients or biopsies from all control groups (almost 0%). High EBV nuclear antigen-1 (EBNA-1) positivity by PCR was found in gastric cancer tissues, but most were not validated by ISH or adjusted for inflammatory severity and lymphocyte infiltration. Only 4 studies tested for EBV antibodies, with large variation in the seropositivities of different antibodies in both cases and controls, and did not find an association between EBV seropositivity and gastric cancer. In summary, tissue-based ISH methods strongly suggest an association between EBV infection and gastric cancer, but PCR method alone is invalid to confirm such association. Very limited evidence from serological studies and the lack of novel antibodies warrant further investiA. Castro, PhD, Jian-Kun Hu, MD, PhD, ner, MD, MPH Abbreviations: BamHI-W = EBV Bam HI W fragment, Bam-M = EBV Bam M fragment, EA-D = diffuse early antigen, EA-R = restricted early antigen, EBER = EBV-encoded small RNA, EBNA = EBV nuclear antigen, EBV = Epstein–Barr virus, ELISA = enzyme-linked immunosorbent assay, IFA = immunofluorescence assay, ISH = in situ hybridization, Nun = n-ulcer disease, PCR = polymerase chain reaction, PUD = peptic ulcer disease, VCA = viral capsid antigen. INTRODUCTION G astric cancer is the third most common cause of cancer death worldwide, with >700,000 deaths estimated to have occurred in 2012. Gastric carcinogenesis is thought to be associated with multiple environmental and genetic factors. Among environmental factors, infection with the bacterium Helicobacter pylori is an established main risk factor. However, increasing evidence suggests that a subset of gastric cancers is associated to Epstein–Barr virus (EBV) infection. Recent cancer genome atlas research has provided a molecular classification defining EBV-positive gastric cancer as a specific subtype. EBV can be found in the malignant epithelial cells of gastric adenocarcinomas. Positivities and characteristics of the EBV-positive cancers have been summarized previously (supplementary Table 1, http://links.lww.com/MD/A257). However, the positivity of EBV infection in normal gastric mucosa, and other gastric diseases, such as dyspepsia, gastritis and peptic ulcer, is largely unexplored. A recent study found all normal gastric mucosa samples from healthy individuals EBV RNA-negative, whereas positivity was 46% in tissues with gastritis, with frequent infiltration of EBV infection. These patterns suggest that EBV infection might be associated with induction of persistent gastric mucosa inflammation and subsequent carcinogenesis. In this systematic review, we aim to provide a comprehensive overview on published epidemiological studies based on in situ hybridization (ISH), polymerase chain reaction (PCR) or serology, comparing EBV nucleic acids positivity in gastric cancer tissues and in adjacent non-tumor tissues; EBV nucleic acids positivity in gastric cancer tissues and in non-tumor mucosa from healthy individuals, patients with benign gastric diseases, or deceased individuals; and EBV seropositivity among gastric cancer patients and healthy controls.