Accumulated studies have been performed to assess the correlation between EBV infection and the prognosis of GC[47]. Some studies have reported that EBV infection predicted better OS in GC patients after surgery[27, 48]. On the contrary, some recent studies still draw different conclusions which showed worse prognostic value of EBV infection for GC patients[35, 49] .Thus, the prognostic value of the EBV remains inconclusive in GC.
Usually, the gold standard of EBV detection method is EBER with accurate localization and strong specificity[50]. The positive rate of PCR can be up to 80%[51], which were higher than that of EBER (about 10%). However, PCR or RNA sequencing may be not reliable due to the presence of intratumoral and peritumoral lymphocytes which may have EBV infection and this limitation cannot be solved by microdissection[52]. Therefore, the present meta-analysis was conducted to investigate the prognostic value of EBV infection with detection method of EBER in GC patients.
35 studies involving 26163 patients in our study were included, and the results showed that EBV-positive patients had a better OS than EBV-negative patients (HR: 0.72, 95% CI: 0.59–0.84, P < 0.001), which was similar to the results of a previous international pooled analysis[53], indicating that EBV-positive GC patients have a better prognosis. The better prognosis of EBV-positive patients may be due to tumor microenvironment and chemotherapy[54].
Some studies have shown that there was no survival difference in EBV-positive patients and EBV-negative patients after surgery and chemotherapy, but EBV-positive patients performed better to chemotherapy with 5-fluorouracil and platinum[55, 56]. Although it has not been proven, EBV-related antigens may help enhance effects of chemotherapy-induced neoantigens and improve survival [57].
EBV-positive GC has a unique tumor microenvironment. EBV-positive GC contains abundant CD8 + tumor-infiltrating lymphocytes (TILs), which enhanced anti-tumor immunity by eliminating EBV-positive tumor cells[58]. In addition, the Asian Cancer Research Group (ACRG) classification also supported the good prognosis of EBV-positive GC patients, because EBV-positive GC was more often included in the microsatellite stable/TP53+ (MSS/P53+) subtype, and together with microsatellite unstable (MSI) adenocarcinoma, which showing the best survival rate[59]. Therefore, EBV-positive GC patients seems to have a better prognosis, but the specific mechanism still needs to be studied.
Our research showed that the prognosis of EBV-positive patients was better than EBV-negative patients among Asians and Americans, while no difference was detected for patients in European. Inconsistent with our research, Xuechao Liu’s study found that the prognosis of EBV-positive patients in Americans were similar to the prognosis of EBV-negative patients[7]. The inconsistency of prognostic effects among American studies may be due to the fact that we did not include an article reporting Risk Ratio and an affiliated study as Xuechao Liu’s study reported[7]. So far, the root cause of these regional differences is still unclear. One possible reason is that phylogeographic diversity of EBV strains in genetic difference (especially in the BamHI–I fragment and the XhoI restriction sites) cause different survival effects[60].
Stratified subgroup analyses were also conducted by statistical method. We discovered that the protective effect of EBV infection still existed both in univariate analysis and multivariate analysis, similar to the results of an international pooled analysis of 13 studies[53]. We included 35 studies, strengthening the reliability that patients with EBV infection had a better prognosis.
There were also several limitations in our present study. Firstly, studies published with the English language only were included in this meta-analysis, and thus potential publication bias existed. Secondly, the studies included were mostly retrospective, which might be more susceptible to biases. Thirdly, we calculated HR and 95% CI from the overall survival curves when the article did not provide them, which might be a potential source of bias. Therefore, large-scale multicenter and prospective researches are needed.
All in all, EBV infection was associated with better OS in patients with GC. These results differed between studies due to differences in region, which need further study to clarify its prognostic significance.