Association of Epstein–Barr virus antibody levels with precancerous gastric lesions in a high‐risk cohort

Abstract

We evaluated associations between Epstein-Barr virus (EBV) antibody levels and precancerous gastric lesions (chronic atrophic gastritis, intestinal metaplasia, and dysplasia) in 183 subjects from Linqu, China. Immunoglobulin G antibody titers to EBV nuclear antigen (EBNA) and viral capsid antigen (VCA) were determined by two-fold serial dilution using immunofluorescence assays. Histological progression and regression were assessed by gastroscopic examination at the time of phlebotomy and at follow up 2 years later. Antibody titers did not differ significantly among histological diagnoses determined at the time of phlebotomy. However, subjects with dysplasia at follow up had significantly higher geometric mean antibody titers for both anti-VCA and anti-EBNA. Subjects with greater than median antibody levels were more likely to progress between examinations, especially in the subgroup with intestinal metaplasia at the time of phlebotomy (odds ratios W ith an estimated 934 000 incident cases and 700 000 deaths worldwide, gastric carcinoma (GC) is the fourth most common cancer, second only to lung cancer in cancerrelated mortality.[(1) GC rates vary widely throughout the world with the highest rates occurring in eastern Asia. Differences in these rates have been attributed to differences in diet and environmental exposures. The pathogenesis of gastric carcinoma is a multistage process affecting the gastric mucosa.(3) For at least intestinal-type GC, there is thought to be a histological progression of precancerous lesions leading up to GC, beginning with superficial gastritis (SG) and advancing through chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia, and finally to GC. More abnormal lesions are associated with an increased risk of GC. In Linqu, China, individuals diagnosed with dysplasia are more likely than those with SG or CAG to develop GC after 5 years. (4) Infection and colonization of the stomach by the bacterium Helicobacter pylori is an important risk factor in the development of most GC, especially non-cardia GC.(5-7) H. pylori infection is thought to cause the development of CAG and IM, (8) and the eradication of H. pylori results in a reduction in the risk of precancerous gastric lesions.(9) A history of H. pylori infection has been found in most GC cases. (7,10) Other infectious agents may also have a role in GC. In particular, the gammaherpesvirus Epstein-Barr virus (EBV) has been implicated by both molecular and serological evidence. EBV nucleic acids are detectable by polymerase chain reaction or in situ hybridization in a significant percentage of GC tumors from many regions of the world, including 16% of GC tumors in North America, (11) 7% in Japan, (12,13) 9% in Russia, (14) and 10% in Kazakhstan.(15) In a prospective study of Japanese Americans, subjects who developed EBV-positive GC had significantly increased antibody titers to EBV viral capsid antigen (VCA) prior to diagnosis.(16) Moreover, in a case-control study from Japan, patients with EBV-positive gastric cancer had...

Improved survival of gastric cancer with tumour Epstein–Barr virus positivity: an international pooled analysis

“…Interestingly, Tang et al 54 found that compared to uninfected tumours, EBV-positive gastric cancer had significant upregulation of key cellular factors in pathways related to NFKB signalling and immune response. Although seropositivity against EBV infection is nearly ubiquitous in humans, elevated titres against VCA and EBV nuclear antigen (EBNA) have been shown to precede development of preneoplastic55 and neoplastic gastric lesions,56 57 and have been associated with longer gastric cancer survival, particularly for cancers localised to the gastric cardia 58…”

Divergent trends for gastric cancer incidence by anatomical subsite in US adults

“…In particular, Epstein–Barr virus (EBV) has been found in ∼9% of non-cardia gastric cancer cases worldwide 24. The mechanism by which EBV may contribute to gastric carcinogenesis is uncertain, but several lines of evidence support its aetiological role: (1) monoclonality of viral episomes in the tumour25; (2) distinct clinical features of EBV-carrying gastric carcinomas as compared with EBV-negative tumours26; (3) characteristic molecular markers, including specific chromosomal aberrations, a transcription pattern resembling but not identical to nasopharyngeal carcinomas, and expression of the EBV BARF1 gene27; and (4) EBV reactivation preceding clinical presentation of gastric precancerous or cancerous lesions, as indicated by elevated antibodies to viral capsid and nuclear antigens 28 29. EBV-positive tumours are preferentially located in the corpus and other non-antral portions of the stomach,24 30 which may have particular relevance for the shifting subsite distribution we detected.…”

An ELISA method to compute endpoint titers to Epstein–Barr virus and cytomegalovirus: Application to population-based studies

“…EBV VCA titers ≥320 are considered elevated and are correlated with reactivation in immunosuppressed individuals (Horwitz et al, 1985; Jenson, 2011). Other investigators, using EBV VCA titers ≥640 as a cutoff, found an increased risk of disease progression (Schetter et al, 2008). Therefore, the EBV and CMV data was further analyzed by using both cutoffs (i.e., ≥320 and ≥640).…”