Epstein-Barr Virus and Gastric Cancer Risk: A Meta-analysis With Meta-regression of Case-control Studies

  • Bae, Jong-Myon (Department of Preventive Medicine, Jeju National University School of Medicine) ;
  • Kim, Eun Hee (Department of Preventive Medicine, Jeju National University School of Medicine)
  • Received : 2015.11.27
  • Accepted : 2016.02.01
  • Published : 2016.03.31


Objectives: Research on how the risk of gastric cancer increases with Epstein-Barr virus (EBV) infection is lacking. In a systematic review that investigated studies published until September 2014, the authors did not calculate the summary odds ratio (SOR) due to heterogeneity across studies. Therefore, we include here additional studies published until October 2015 and conduct a meta-analysis with meta-regression that controls for the heterogeneity among studies. Methods: Using the studies selected in the previously published systematic review, we formulated lists of references, cited articles, and related articles provided by PubMed. From the lists, only case-control studies that detected EBV in tissue samples were selected. In order to control for the heterogeneity among studies, subgroup analysis and meta-regression were performed. Results: In the 33 case-control results with adjacent non-cancer tissue, the total number of test samples in the case and control groups was 5280 and 4962, respectively. In the 14 case-control results with normal tissue, the total number of test samples in case and control groups was 1393 and 945, respectively. Upon meta-regression, the type of control tissue was found to be a statistically significant variable with regard to heterogeneity. When the control tissue was normal tissue of healthy individuals, the SOR was 3.41 (95% CI, 1.78 to 6.51; I-squared, 65.5%). Conclusions: The results of the present study support the argument that EBV infection increases the risk of gastric cancer. In the future, age-matched and sex-matched case-control studies should be conducted.


  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893-2917.
  2. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat 2015;47(2):127-141.
  3. Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology 2009;137(3):824-833.
  4. Shi J, Qu YP, Hou P. Pathogenetic mechanisms in gastric cancer. World J Gastroenterol 2014;20(38):13804-13819.
  5. Wroblewski LE, Peek RM Jr. Helicobacter pylori in gastric carcinogenesis: mechanisms. Gastroenterol Clin North Am 2013; 42(2):285-298.
  6. Shinozaki-Ushiku A, Kunita A, Fukayama M. Update on Epstein-Barr virus and gastric cancer (review). Int J Oncol 2015; 46(4): 1421-1434.
  7. Chen XZ, Chen H, Castro FA, Hu JK, Brenner H. Epstein-Barr virus infection and gastric cancer: a systematic review. Medicine (Baltimore) 2015;94(20):e792.
  8. Javier RT, Butel JS. The history of tumor virology. Cancer Res 2008;68(19):7693-7706.
  9. Camargo MC, Murphy G, Koriyama C, Pfeiffer RM, Kim WH, Herrera-Goepfert R, et al. Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis. Br J Cancer 2011;105(1):38-43.
  10. International Agency for Research on Cancer (IARC). Agents classified by the IARC monographs, volumes 1-112 [cited 2015 Nov 12]. Available from:
  11. Burke AP, Yen TS, Shekitka KM, Sobin LH. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol 1990;3(3):377-380.
  12. Akiba S, Koriyama C, Herrera-Goepfert R, Eizuru Y. Epstein-Barr virus associated gastric carcinoma: epidemiological and clinicopathological features. Cancer Sci 2008;99(2):195-201.
  13. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513(7517):202-209.
  14. Fukayama M, Hino R, Uozaki H. Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma. Cancer Sci 2008;99(9):1726-1733.
  15. Uozaki H, Fukayama M. Epstein-Barr virus and gastric carcinoma--viral carcinogenesis through epigenetic mechanisms. Int J Clin Exp Pathol 2008;1(3):198-216.
  16. Li S, Du H, Wang Z, Zhou L, Zhao X, Zeng Y. Meta-analysis of the relationship between Epstein-Barr virus infection and clinicopathological features of patients with gastric carcinoma. Sci China Life Sci 2010;53(4):524-530.
  17. Sousa H, Pinto-Correia AL, Medeiros R, Dinis-Ribeiro M. Epstein-Barr virus is associated with gastric carcinoma: the question is what is the significance? World J Gastroenterol 2008; 14(27):4347-4351.
  18. Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 2009;24(3):354-365.
  19. Zong L, Seto Y. CpG island methylator phenotype, Helicobacter pylori, Epstein-Barr virus, and microsatellite instability and prognosis in gastric cancer: a systematic review and meta-analysis. PLoS One 2014;9(1):e86097.
  20. Chen YP, Zhang WN, Chen L, Tang LL, Mao YP, Li WF, et al. Effect of latent membrane protein 1 expression on overall survival in Epstein-Barr virus-associated cancers: a literature-based meta-analysis. Oncotarget 2015;6(30):29311-29323.
  21. Liu X, Liu J, Qiu H, Kong P, Chen S, Li W, et al. Prognostic significance of Epstein-Barr virus infection in gastric cancer: a meta-analysis. BMC Cancer 2015;15:782.
  22. Liang W, Tian H. Hypothetic association between human papillomavirus infection and breast carcinoma. Med Hypotheses 2008;70(2):305-307.
  23. Sterne JA, Harbord RM. Funnel plots in meta-analysis. Stata J 2004;4(2):127-141.
  24. Harbord RM, Higgins JP. Meta-regression in Stata. Stata J 2008;8(4):493-519.
  25. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 2006;25(20):3443-3457.
  26. Bae JM. Narrative reviews. Epidemiol Health 2014;36:e2014018.
  27. Bae JM. Human papillomavirus 16 infection as a potential risk factor for prostate cancer: an adaptive meta-analysis. Epidemiol Health 2015;37:e2015005.
  28. Bae JM, Kim EH. Hormone replacement therapy and risk of breast cancer in Korean women: a quantitative systematic review. J Prev Med Public Health 2015;48(5):225-230.
  29. Sakuma K, Uozaki H, Chong JM, Hironaka M, Sudo M, Ushiku T, et al. Cancer risk to the gastric corpus in Japanese, its correlation with interleukin-1beta gene polymorphism (+3953*T) and Epstein-Barr virus infection. Int J Cancer 2005;115(1):93-97.
  30. Yuan XY, Wang MY, Wang XY, Chang AY, Li J. Non-detection of Epstein-Barr virus and Human Papillomavirus in a region of high gastric cancer risk indicates a lack of a role for these viruses in gastric carcinomas. Genet Mol Biol 2013;36(2):183-184.
  31. Koshiol J, Qiao YL, Mark SD, Dawsey SM, Abnet CC, Kamangar F, et al. Epstein-Barr virus serology and gastric cancer incidence and survival. Br J Cancer 2007;97(11):1567-1569.
  32. Kim Y, Shin A, Gwack J, Ko KP, Kim CS, Park SK, et al. Epstein-Barr virus antibody level and gastric cancer risk in Korea: a nested case-control study. Br J Cancer 2009;101(3):526-529.
  33. Schetter AJ, You WC, Lennette ET, Gail MT, Rabkin CS. Association of Epstein-Barr virus antibody levels with precancerous gastric lesions in a high-risk cohort. Cancer Sci 2008; 99(2):350-354.
  34. Tokunaga M, Land CE, Uemura Y, Tokudome T, Tanaka S, Sato E. Epstein-Barr virus in gastric carcinoma. Am J Pathol 1993; 143(5):1250-1254.
  35. Gurtsevich VE, Galetskiĭ SA, Nered SN, Novikova EV, Iakovleva LS, Land ChE, et al. Detection and characterization of gastric carcinoma associated with Epstein-Barr herpes virus. Vestn Ross Akad Med Nauk 1999;(3):56-59 (Russian).
  36. Yanai H, Nishikawa J, Mizugaki Y, Shimizu N, Takada K, Matsusaki K, et al. Endoscopic and pathologic features of Epstein-Barr virus-associated gastric carcinoma. Gastrointest Endosc 1997; 45(3):236-342.
  37. Luo B, Wang Y, Wang XF, Liang H, Yan LP, Huang BH, et al. Expression of Epstein-Barr virus genes in EBV-associated gastric carcinomas. World J Gastroenterol 2005;11(5):629-633.
  38. Shukla SK, Prasad KN, Tripathi A, Singh A, Saxena A, Ghoshal UC, et al. Epstein-Barr virus DNA load and its association with Helicobacter pylori infection in gastroduodenal diseases. Braz J Infect Dis 2011;15(6):583-590.
  39. Shukla SK, Prasad KN, Tripathi A, Ghoshal UC, Krishnani N, Husain N. Expression profile of latent and lytic transcripts of epstein-barr virus in patients with gastroduodenal diseases: a study from northern India. J Med Virol 2012;84(8):1289-1297.
  40. Imai S, Koizumi S, Sugiura M, Tokunaga M, Uemura Y, Yamamoto N, et al. Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc Natl Acad Sci U S A 1994;91(19):9131-9135.
  41. Galetsky SA, Tsvetnov VV, Land CE, Afanasieva TA, Petrovichev NN, Gurtsevitch VE, et al. Epstein-Barr-virus-associated gastric cancer in Russia. Int J Cancer 1997;73(6):786-789.<786::AID-IJC2>3.0.CO;2-Z
  42. Ishii HH, Gobe GC, Yoneyama J, Mukaide M, Ebihara Y. Role of p53, apoptosis, and cell proliferation in early stage Epstein-Barr virus positive and negative gastric carcinomas. J Clin Pathol 2004;57(12):1306-1311.
  43. Wang Y, Luo B, Zhao P, Huang BH. Expression of Epstein-Barr virus genes in EBV-associated gastric carcinoma. Ai Zheng 2004;23(7):782-787 (Chinese).
  44. Saxena A, Nath Prasad K, Chand Ghoshal U, Krishnani N, Roshan Bhagat M, Husain N. Association of Helicobacter pylori and Epstein-Barr virus with gastric cancer and peptic ulcer disease. Scand J Gastroenterol 2008;43(6):669-674.
  45. Shibata D, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol 1992;140(4):769-774.
  46. Shibata D, Hawes D, Stemmermann GN, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma among Japanese Americans in Hawaii. Cancer Epidemiol Biomarkers Prev 1993; 2(3):213-217.
  47. Fukayama M, Hayashi Y, Iwasaki Y, Chong J, Ooba T, Takizawa T, et al. Epstein-Barr virus-associated gastric carcinoma and Epstein-Barr virus infection of the stomach. Lab Invest 1994; 71(1):73-81.
  48. Ott G, Kirchner T, Müller-Hermelink HK. Monoclonal Epstein-Barr virus genomes but lack of EBV-related protein expression in different types of gastric carcinoma. Histopathology 1994; 25(4):323-329.
  49. Shousha S, Luqmani YA. Epstein-Barr virus in gastric carcinoma and adjacent normal gastric and duodenal mucosa. J Clin Pathol 1994;47(8):695-698.
  50. Yuen ST, Chung LP, Leung SY, Luk IS, Chan SY, Ho J. In situ detection of Epstein-Barr virus in gastric and colorectal adenocarcinomas. Am J Surg Pathol 1994;18(11):1158-1163.
  51. Anwar K, Nakakuki K, Imai H, Inuzuka M. Infection of human papillomavirus (hpv) and Epstein-Barr-virus (EBV) and p53 overexpression in human gastric-carcinoma. Int J Oncol 1995; 7(2):391-397.
  52. Harn HJ, Chang JY, Wang MW, Ho LI, Lee HS, Chiang JH, et al. Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan. Hum Pathol 1995;26(3):267-271.
  53. Gulley ML, Pulitzer DR, Eagan PA, Schneider BG. Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Hum Pathol 1996;27(1):20-27.
  54. Moritani S, Kushima R, Sugihara H, Hattori T. Phenotypic characteristics of Epstein-Barr-virus-associated gastric carcinomas. J Cancer Res Clin Oncol 1996;122(12):750-756.
  55. Simon G, Francescutti C, Brusin S, Rosa F. Variation in drug prescription costs and general practitioners in an area of North-East Italy. The use of current data. Epidemiol Prev 1994;18(61):224-229 (Italian).
  56. Shin WS, Kang MW, Kang JH, Choi MK, Ahn BM, Kim JK, et al. Epstein-Barr virus-associated gastric adenocarcinomas among Koreans. Am J Clin Pathol 1996;105(2):174-181.
  57. Durmaz R, Aydin A, Köroglu M, Durmaz B, Ciralik H. Investigation of the relationship between Epstein-Barr virus and ordinary gastric carcinoma using the nested polymerase chain reaction. Acta Virol 1998;42(6):359-363.
  58. Hsieh LL, Lin PJ, Chen TC, Ou JT. Frequency of Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan. Cancer Lett 1998;129(2):125-129.
  59. Kume T, Oshima K, Shinohara T, Takeo H, Yamashita Y, Shirakusa T, et al. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus-associated gastric carcinoma. Histopathology 1999;34(6):502-509.
  60. Wan R, Gao MQ, Gao LY, Chen BF, Cai QK. In situ detection of Epstein Barr virus in gastric carcinoma tissue in China high-risk area. World J Gastroenterol 1999;5(6):531-532.
  61. Chapel F, Fabiani B, Davi F, Raphael M, Tepper M, Champault G, et al. Epstein-Barr virus and gastric carcinoma in Western patients: comparison of pathological parameters and p53 expression in EBV-positive and negative tumours. Histopathology 2000;36(3):252-261.
  62. Corvalan A, Koriyama C, Akiba S, Eizuru Y, Backhouse C, Palma M, et al. Epstein-Barr virus in gastric carcinoma is associated with location in the cardia and with a diffuse histology: a study in one area of Chile. Int J Cancer 2001;94(4):527-530.
  63. Lo YM, Chan WY, Ng EK, Chan LY, Lai PB, Tam JS, et al. Circulating Epstein-Barr virus DNA in the serum of patients with gastric carcinoma. Clin Cancer Res 2001;7(7):1856-1859.
  64. Luqmani YA, Linjawi SO, Shousha S. Detection of Epstein-Barr virus in gastrectomy specimens. Oncol Rep 2001;8(5):995-999.
  65. Kang GH, Lee S, Kim WH, Lee HW, Kim JC, Rhyu MG, et al. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol 2002;160(3):787-794.
  66. Oda K, Koda K, Takiguchi N, Nunomura M, Seike K, Miyazaki M. Detection of Epstein-Barr virus in gastric carcinoma cells and surrounding lymphocytes. Gastric Cancer 2003;6(3):173-178.
  67. Lee MA, Hong YS, Kang JH, Lee KS, You JY, Lee KY, et al. Detection of Epstein-Barr virus by PCR and expression of LMP1, p53, CD44 in gastric cancer. Korean J Intern Med 2004;19(1):43-47.
  68. Lopes LF, Bacchi MM, Elgui-de-Oliveira D, Zanati SG, Alvarenga M, Bacchi CE. Epstein-Barr virus infection and gastric carcinoma in São Paulo State, Brazil. Braz J Med Biol Res 2004; 37(11):1707-1712.
  69. Alipov G, Nakayama T, Nakashima M, Wen CY, Niino D, Kondo H, et al. Epstein-Barr virus-associated gastric carcinoma in Kazakhstan. World J Gastroenterol 2005;11(1):27-30.
  70. Herrera-Goepfert R, Akiba S, Koriyama C, Ding S, Reyes E, Itoh T, et al. Epstein-Barr virus-associated gastric carcinoma: evidence of age-dependence among a Mexican population. World J Gastroenterol 2005;11(39):6096-6103.
  71. von Rahden BH, Langner C, Brücher BL, Stein HJ, Sarbia M. No association of primary adenocarcinomas of the small bowel with Epstein-Barr virus infection. Mol Carcinog 2006; 45(5):349-352.
  72. Truong CD, Feng W, Li W, Khoury T, Li Q, Alrawi S, et al. Characteristics of Epstein-Barr virus-associated gastric cancer: a study of 235 cases at a comprehensive cancer center in U.S.A. J Exp Clin Cancer Res 2009;28:14.
  73. Chen JN, Ding YG, Feng ZY, Li HG, He D, Du H, et al. Association of distinctive Epstein-Barr virus variants with gastric carcinoma in Guangzhou, southern China. J Med Virol 2010; 82(4):658-667.
  74. de Aquino PF, Carvalho PC, da Gama Fischer JS, de Souza AQ, Viana JS, Chalub SR, et al. Epstein-Barr virus DNA associated with gastric adenocarcinoma and adjacent non-cancerous mucosa in patients from Manaus, Brazil. Genet Mol Res 2012; 11(4):4442-4446.
  75. Zhao J, Jin H, Cheung KF, Tong JH, Zhang S, Go MY, et al. Zinc finger E-box binding factor 1 plays a central role in regulating Epstein-Barr virus (EBV) latent-lytic switch and acts as a therapeutic target in EBV-associated gastric cancer. Cancer 2012; 118(4):924-936.
  76. de Souza CR, de Oliveira KS, Ferraz JJ, Leal MF, Calcagno DQ, Seabra AD, et al. Occurrence of Helicobacter pylori and Epstein-Barr virus infection in endoscopic and gastric cancer patients from Northern Brazil. BMC Gastroenterol 2014;14:179.
  77. Weinstein SJ, Stolzenberg-Solomon R, Pietinen P, Taylor PR, Virtamo J, Albanes D. Dietary factors of one-carbon metabolism and prostate cancer risk. Am J Clin Nutr 2006;84(4):929-935.