Antibodies Against Epstein-Barr Virus as Disease Markers of Gastric Cancer: A Systematic Review

Abstract

Introduction: Gastric cancer is the fourth deadliest cancer worldwide. Due to the lack of specific early symptoms and noninvasive methods for early detection, the prognosis of gastric cancer patients is poor. Gastric cancer has a well-recognized infectious etiology, with Helicobacter pylori and Epstein-Barr Virus being the main associated infectious agents. Although other Epstein-Barr Virus-associated malignancies often manifest with abnormal levels of anti-Epstein-Barr Virus antibodies, it is not clear whether this is also true for gastric cancer. Potentially, these antibodies could serve as a noninvasive tool for gastric cancer screening or as markers for gastric cancer risk and provide a better understanding of the participation of Epstein-Barr Virus in the development of this neoplasm. Methods: We conducted a systematic review of articles analyzing anti-Epstein-Barr Virus serology in gastric cancer and precursor lesions following PRISMA guidelines. Patients were classified according to the Correa cascade of gastric lesions and whether they were positive or negative by EBER-in situ hybridization (Epstein-Barr Virus-associated gastric cancer and Epstein-Barr Virus-nonassociated gastric cancer, respectively). Results: We retrieved 16 articles involving 9735 subjects from 12 different countries and 4 databases, PubMed, SciELO, Scopus, and Google Scholar. Higher antibody titers were observed not only in Epstein-Barr Virus-associated gastric cancer than in Epstein-Barr Virus-nonassociated gastric cancer but also in Epstein-Barr Virus-nonassociated gastric cancer and gastric cancer-precursor lesions when compared with patients with mild dyspepsia or healthy controls. In all cases, the associations were predominantly with antibodies directed against lytic cycle antigens. Conclusion: Data support the role of Epstein-Barr Virus lytic reactivation in the development of advanced gastric lesions. However, more studies are needed to confirm these associations, particularly the association with lesions considered negative by EBER-in situ hybridization, and to establish a set of antibodies and thresholds indicative of enhanced risk to develop these lesions.

Keywords: EBV; EBVaGC; antibodies; gastric cancer; gastric cancer risk; serology.

Figure 1.

Flowchart of the study selection process for the systematic review.

Figure 2.

Association between anti-Epstein–Barr Virus (EBV) serology and EBV-associated gastric cancer. Two types of statistical tests are represented, comparisons between antibody levels and odds ratios based on either seropositivity or levels above specified cut-off values. Left panel: Circles and squares indicate a significant or nonsignificant difference in median antibody titers, respectively. Right panel: Forest plot showing reported odds ratios (ORs) and respective 95% confidence interval and symbol area representing the number of subjects included for associations with high antibody titers. The studies by Shinkura et al, Levine et al, Imai et al, and Szkaradkiewicz et al did not specify which EBNA or EA antigen was assessed and were assigned to EBNA1 and EA-D, respectively.

Figure 3.

Association of anti-Epstein–Barr Virus (EBV) serology and gastric cancer or preneoplastic lesions of unknown EBV-status. Two types of statistical tests are represented, comparisons between antibody levels and odds ratios based on either seropositivity or levels above specified cutoff values. Left panel: Circles and squares indicate a significant or nonsignificant difference in median antibody titers, respectively. Right panel: Forest plot showing reported odds ratios (ORs) and respective 95% confidence interval and symbol area representing the number of subjects included for associations with high antibody titers. The studies by Aragones et al, Varga et al, and Kayamba et al did not specify the antibody isotype and were assigned to IgG. Schetter et al, Varga et al, and Pachnia et al did not specify which EBNA or EA antigen was assessed and were assigned to EBNA1 and EA-D, respectively.