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Clinicopathological characteristics and prognosis of Epstein-Barr virus–associated gastric cancer

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Abstract

Objective

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS).

Methods

A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis.

Results

Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%.

Conclusion

EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. World Health Organization (WHO). Global Health Estimates 2020: Deaths by Cause, Age, Sex, by Country and by Region, 2000–2019. WHO (2020) Accessed December 11, 2020. whowww.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death

  2. Costache S, Sajin M, Wedden S et al A consolidated working classification of gastric cancer for histopathologists (Review). Biomed Rep. 2023 July 19;19(3):58

  3. Jia X, Guo T, Li Z et al (2021) Clinicopathological and Immunomicroenvironment Characteristics of Epstein-Barr Virus-Associated Gastric Cancer in a Chinese Population. Front Oncol 10:586752

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lieberman PM (2016) Epigenetics and Genetics of Viral Latency. Cell Host Microbe 19(5):619–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu J, Murakami M, Verma SC et al (2011) Epstein-Barr Virus nuclear antigen 1 (EBNA1) confers resistance to apoptosis in EBV-positive B-lymphoma cells through up-regulation of survivin. Virology 410(1):64–75

    Article  CAS  PubMed  Google Scholar 

  6. Frappier L (2012) Contributions of Epstein-Barr nuclear antigen 1 (EBNA1) to cell immortalization and survival. Viruses 4(9):1537–1547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Münz C (2019) Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nat Rev Microbiol 17(11):691–700

    Article  PubMed  Google Scholar 

  8. Shinozaki-Ushiku A, Kunita A, Fukayama M (2015) Update on Epstein-Barr virus and gastric cancer (review). Int J Oncol 46(4):1421–1434. https://doi.org/10.3892/ijo.2015.2856

    Article  CAS  PubMed  Google Scholar 

  9. Farrell PJ Epstein-Barr Virus and Cancer. Annu Rev Pathol 2019 January 24;14:29–53

  10. Burke AP, Yen TS, Shekitka KM, Sobin LH (1990) Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol 3(3):377–380

    CAS  PubMed  Google Scholar 

  11. Roy S (2021) Physicians’ Dilemma of False-Positive RT-PCR for COVID-19: a Case Report. SN Compr Clin Med 3(1):255–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. AbuSalah MAH, Gan SH, Al-Hatamleh MAI et al (2020) Recent Advances in Diagnostic Approaches for Epstein-Barr Virus. Pathogens 9(3):226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Owliaee I, Khaledian M, Boroujeni AK et al (2023) Engineered small extracellular vesicles as a novel platform to suppress human oncovirus-associated cancers. Infect Agents Cancer 69(18):1750–9378

    Google Scholar 

  14. Tokunaga M, Uemura Y, Tokudome T et al (1993 Oct) Epstein-Barr virus virus-related gastric cancer in Japan: a molecular patho-epidemiological study. Acta Pathol Jpn 43(10):574–581

  15. Chen JN, Ding YG, Feng ZY et al (2010) Association of distinctive Epstein-Barr virus variants with gastric carcinoma in Guangzhou, southern China. J Med Virol 82(4):658–667

    Article  CAS  PubMed  Google Scholar 

  16. Qiu MZ, He CY, Lu SX et al (2020) Prospective observation: Clinical utility of plasma Epstein-Barr virus DNA load in EBV-associated gastric carcinoma patients. Int J Cancer 146(1):272–280

    Article  CAS  PubMed  Google Scholar 

  17. Lee JH, Kim SH, Han SH et al (2009) Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 24(3):354–365

    Article  PubMed  Google Scholar 

  18. Camargo MC, Kim WH, Chiaravalli AM et al (2014) Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 63(2):236–243

    Article  PubMed  Google Scholar 

  19. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209

    Article  Google Scholar 

  20. Au WY, Pang A, Chan EC et al (2005) Epstein-barr virus-related gastric adenocarcinoma: an early secondary cancer post hemopoietic stem cell transplantation. Gastroenterology 129(6):2058–2063

    Article  PubMed  Google Scholar 

  21. Hofmann M, Stoss O, Shi D et al (2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52(7):797–805

    Article  CAS  PubMed  Google Scholar 

  22. Kulangara K, Zhang N, Corigliano E et al (2019) Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer. Arch Pathol Lab Med 143(3):330–337

    Article  CAS  PubMed  Google Scholar 

  23. Song HJ, Srivastava A, Lee J et al (2010) Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology 139(1):84–92e2

    Article  PubMed  Google Scholar 

  24. Li GH, Zhou ZH, Wang ZX et al (2023) Assessing Epstein-Barr virus in gastric cancer: clinicopathological features and prognostic implications. Infect Agent Cancer 18:11

    Article  PubMed  PubMed Central  Google Scholar 

  25. Atri-Schuller A, Abushukair H, Cavalcante L et al (2022) Tumor Molecular and Microenvironment Characteristics in EBV-Associated Malignancies as Potential Therapeutic Targets: Focus on Gastric Cancer. Curr Issues Mol Biol 44(11):5756–5767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Salnikov MY, Fonseca GJ, Mymryk JS (2023) Differences in the Tumor Microenvironment of EBV-Associated Gastric Cancers Revealed Using Single-Cell Transcriptome Analysis. Cancers (Basel) 15(12):3178

    Article  CAS  PubMed  Google Scholar 

  27. Wong Y, Meehan MT, Burrows SR et al (2022) Estimating the global burden of Epstein-Barr virus-related cancers. J Cancer Res Clin Oncol 148(1):31–46

    Article  PubMed  Google Scholar 

  28. Tatematsu D, Akao M, Park H et al (2023 March) Relationship between the inclusion/exclusion criteria and sample size in randomized controlled trials for SARS-CoV-2 entry inhibitors. J Theor Biol 21:561:111403

  29. Chen JN, He D, Tang F et al (2012) Epstein-Barr virus-associated gastric carcinoma: a newly defined entity. J Clin Gastroenterol 46(4):262–271

    Article  CAS  PubMed  Google Scholar 

  30. Van Cutsem E, Bang YJ, Feng-Yi F et al (2015) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 18(3):476–484

    Article  PubMed  Google Scholar 

  31. Chakravorty S, Afzali B, Kazemian M (2022 October) EBV-associated diseases: Current therapeutics and emerging technologies. Front Immunol 27:13:1059133

  32. Dugan JP, Coleman CB, Haverkos B (2019 March) Opportunities to Target the Life Cycle of Epstein-Barr Virus (EBV) in EBV-Associated Lymphoproliferative Disorders. Front Oncol 15:9:127

  33. Sukawa Y, Yamamoto H, Nosho K et al (2012 December) Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer. World J Gastroenterol 7(45):6577–6586

  34. Zhang YW, Zhao XX, Tan C et al (2015) Epstein-Barr virus latent membrane protein 2A suppresses the expression of HER2 via a pathway involving TWIST and YB-1 in Epstein-Barr virus-associated gastric carcinomas. Oncotarget 6(1):207–220

    Article  PubMed  Google Scholar 

  35. Lee HS, Chang MS, Yang HK et al (2004) Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma. Clin Cancer Res. March 1;10(5):1698–1705

  36. Park JH, Kim EK, Kim YH et al (2016) Epstein-Barr virus positivity, not mismatch repair- deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer. Gastric Cancer 19(4):1041–1051

    Article  CAS  PubMed  Google Scholar 

  37. Osumi H, Kawachi H, Murai K et al (2019) Risk stratification for lymph node metastasis using Epstein-Barr virus status in submucosal invasive (pT1) gastric cancer without lymphovascular invasion: a multicenter observational study. Gastric Cancer 22(6):1176–1182

    Article  CAS  PubMed  Google Scholar 

  38. Zhang Y, Yang Y, Chen Y et al (2022) PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer. Front Immunol 13:1060497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mishima S, Kawazoe A, Nakamura Y et al (2019) Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer. J Immunother Cancer 7(1):24

    Article  PubMed  PubMed Central  Google Scholar 

  40. Tsao LC, Force J, Hartman ZC Mechanisms of Therapeutic Antitumor Monoclonal Antibodies. Cancer Res 2021 September 15;81(18):4641–4651

Download references

Funding

This work was supported by Xuzhou Medical Key Talent Training Project (XWRCHT20220068); Xuzhou Medical University Hospital Development Fund Innovation Team Project (XYFC2021001), and the surface project (XYFM2021014).

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Author notes

  1. Lin-lin Li, Ao-yang Yu and Mei Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China

    Lin-lin Li

  2. Graduate School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Ao-yang Yu & Lu-yao Ma

  3. Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, 221005, Jiangsu, China

    Mei Zhu

  4. Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China

    Meng-han Cao, Wen-lou Liu, Xiao-bing Qin, Chao Gao, Zheng-xiang Han & Hong-mei Wang

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  1. Lin-lin Li
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Contributions

L.L, A.Y., M.Z., and H.W. conceptualized and designed the study and drafted the initial manuscript. L.M., M.C., W.L., X.Q., and C.G. collected the data and carried out the initial analyses. Z.H. and H.W. critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Zheng-xiang Han or Hong-mei Wang.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This study was approved by the Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY2021-KL063-01).

Additional information

Communicated by Zhongjie Shi.

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Li, Ll., Yu, Ay., Zhu, M. et al. Clinicopathological characteristics and prognosis of Epstein-Barr virus–associated gastric cancer. Arch Virol 169, 114 (2024). https://doi.org/10.1007/s00705-024-06033-3

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