Rate of Epstein-Barr Virus in Gastric Adenocarcinoma in Egyptian Patients in View of the WHO Classification and Correlation with p16 Immunoreactivity

Authors

  • Safia Samir Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, Egypt
  • Hend Okasha Ahmed Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Giza, Egypt
  • Tarek M. Diab Department of Parasitology, Theodor Bilharz Research Institute, Giza, Egypt
  • Amr Mostafa Department of Surgery, Theodor Bilharz Research Institute, Giza, Egypt
  • Hesham A. Elmeligy Department of Surgery, Theodor Bilharz Research Institute, Giza, Egypt
  • Amira Kamel Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt
  • Heba Khalil Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt

DOI:

https://doi.org/10.3889/oamjms.2022.9700

Keywords:

Epstein-Barr virus, Gastric adenocarcinoma, qPCR, Immunohistochemistry, p16 protein

Abstract

BACKGROUND AND AIM: Gastric cancer (GC) is one of the top causes of cancer-related deaths worldwide. According to the Cancer Genome Atlas, there are four subtypes of GC, with the Epstein-Barr virus (EBV) subtype accounting for about 10% of cases. EBV infection causes EBV-associated GC (EBVaGC). The previous research suggested that the presence of the EBV viral genome in gastric carcinomas could be used as a surrogate marker for targeted therapy and optimal GC treatment.

AIM: We aimed to explore the rate of EBV involvement in gastric carcinogenesis from molecular perspective view and to evaluate the role of the tumor-suppressor protein p16 as a marker for diagnosis in GC Egyptian patients in relation to EBV infection.

METHODS: One hundred-four surgically resected GC cases were analyzed. Two methods including quantitative real-time polymerase chain reaction (qPCR) for detecting EBV-derived latent membrane protein-1 (LMP-1) and Epstein-Barr nuclear antigen-1 (EBNA-1) genes as well as immunohistochemistry (IHC) detection of LMP-1 protein and p16 protein on paraffinized tissue blocks were applied.

RESULTS: Using IHC, p16 protein was presented in 90/104 (86.5%) of the GC cases, and EBV LMP-1 was detected in 4 cases (3.84%). qPCR detected 14 cases positive for EBV (13.46%). In EBV positive cases detected using qPCR, no expression of p16 was detected.

CONCLUSION: EBVaGC has a low incidence in Egypt; loss of p16 expression was recognized in EBVaGC and could be considered as a promising biomarker of EBVaGC. The combination of the two methods IHC and qPCR in addition to p16 is recommended for improving the accuracy of identification of infected cancer.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Sun K, Jia K, Lv H, Wang SQ, Wu Y, Lei H, et al. EBV-positive gastric cancer: Current knowledge and future perspectives. Front Oncol. 2020;10:583463. https://doi.org/10.3389/fonc.2020.583463 PMid:33381453

American Cancer Society-Cancer Facts and Amp; Statistics. Georgia: American Cancer Society-Cancer Facts and amp; Statistics; 2020.

Dasari S, Bernard Tchounwou P. Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 2014;740:364-78. https://doi.org/10.1016/j.ejphar.2014.07.025 PMid:25058905

Siebenhüner AR, Dosso D, Winder T, Burg V, Borner M. Pederiva S, et al. Advanced gastric cancer: Current treatment landscape and a future outlook for sequential and personalized guide: Swiss expert statement article. 2021;44(9):485-94. https://doi.org/10.1159/000518107 PMid:34350899

Global Cancer Observatory. Source: Globocan 2020. Egypt: Global Cancer Observatory; 2020.

Cancer Rates in Egypt to Increase Three Times by 2050-Egypt Today; 2017.

Badawi H, El Said M, Samir S, Ismail A, Badawy A, Barakat A, et al. Prevalence of human papillomavirus genotypes among egyptian patients with cancer bladder. J Int Pharm Res. 2018;45:203.

Morales-Sánchez A, Fuentes-Pananá EM. Human viruses and cancer. Viruses. 2014;6(10):4047-79. https://doi.org/10.3390/v6104047 PMid:25341666

Camargo MC, Kim KM, Matsuo K, Torres J, Liao LM, Morgan DR, et al. Anti-helicobacter pylori antibody profiles in Epstein-barr virus (EBV)-positive and EBV-negative gastric cancer. Helicobacter. 2016;21(2):153-7. https://doi.org/10.1111/hel.12249 PMid:26251258

Osumi H, Kawachi H, Yoshio T, Ida S, Yamamoto N, Horiuchi Y, et al. Epstein-barr virus status is a promising biomarker for endoscopic resection in early gastric cancer: proposal of a novel therapeutic strategy. J Gastroenterol. 2019;54(9):774-83. https://doi.org/10.1007/s00535-019-01562-0 PMid:30826866

Garattini SK, Basile D, Cattaneo M, Fanotto V, Ongaro E, Bonotto M, et al. Molecular classifications of gastric cancers: Novel insights and possible future applications. World J Gastrointest Oncol. 2017;9(5):194-8. https://doi.org/10.4251/wjgo.v9.i5.194 PMid:28567184

Brasil-Costa I, de Souza CR, Costa IB, dos Santos LF, Paixão LC, Polaro AA, et al. Detection of Epstein-barr virus in gastric adenocarcinoma: qPCR and FISH comparison. Med Microbiol Immunol. 2022;211(1):29-36. https://doi.org/10.1007/s00430-021-00724-3 PMid:34862564

Zhao Y, Zhang J, Cheng AS, Yu J, To KF, Kang W. Gastric cancer: genome damaged by bugs. Oncogene. 2020;39(17):3427-42. https://doi.org/10.1038/s41388-020-1241-4 PMid:32123313

Liang C, Wu HM, Yu WM, Chen W. Research status on immunotherapy trials of gastric cancer. World J Clin Cases. 2021;9(21):5782-93. https://doi.org/10.12998/wjcc.v9.i21.5782 PMid:34368297

Bass AJ, Thorsson V, Shmulevich I, Reynolds SM, Miller M, Bernard B, et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-9. https://doi.org/10.1038/nature13480 PMid:25079317

Fukayama M, Ushiku T. Epstein-barr virus-associated gastric carcinoma. Pathol Res Pract. 2011;207(9):529-37. https://doi.org/10.1016/j.prp.2011.07.004

Chen JN, He D, Tang F, Shao CK. Epstein-barr virus-associated gastric carcinoma: A newly defined entity. J Clini Gastroenterol. 2012;46(4):262-71. https://doi.org/10.1097/MCG.0b013e318249c4b8 PMid:22392024

Amoueian S, Attaranzadeh A, Gholamimoallem Z, Sadeghi M, Hashemi SM, Allahyari A. Epstein-barr virus infection in adult patients with gastric cancer in Northeast of Iran. Indian J Med Paediatr Oncol. 2018;39(2):206-209.

Mendaza S, Fernández-Irigoyen J, Santamaría E, Zudaire T, Guarch R, Guerrero-Setas D, et al. Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix. Int J Mol Sci. 2020;21(6):2125. https://doi.org/10.3390/ijms21062125 PMid:32204550

QI ZL, Han XQ, HU J, Wang GH, Gao JW, Wang X, et al. Comparison of three methods for the detection of Epstein-barr virus in Hodgkin’s lymphoma in paraffin-embedded tissues. Mol Med Rep. 2013;7(1):89-92. https://doi.org/10.3892/mmr.2012.1163 PMid:23128841

Ojima H, Saito K, Yamauchi H, Yamaki E, Idetu A, Hosouchi Y, et al. P16 protein abnormality in Epstein-barr virus-associated gastric carcinomas. Anticancer Res. 2006;26(2A):933-7. PMid:16619489

Konforte D, Simard N, Paige CJ. Interleukin-21 regulates expression of key Epstein-Barr virus oncoproteins, EBNA2 and LMP1, in infected human B cells. Virology. 2008;374(1):100-13. https://doi.org/10.1016/j.virol.2007.12.027 PMid:18222514

Rao X, Huang X, Zhou Z, Lin X. An improvement of the 2ˆ(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath. 2013;3(3):71-85. PMid:25558171

Xie T, Liu Y, Zhang Z, Zhang X, Gong J, Qi C, et al. Positive status of Epstein-barr virus as a biomarker for gastric cancer immunotherapy: A prospective observational study. J Immunother. 2020;43(4):139-44. https://doi.org/10.1097/CJI.0000000000000316 PMid:32134806

Evers DL, He J, Kim YH, Mason JT, O’Leary TJ. Paraffin embedding contributes to RNA aggregation, reduced RNA yield, and low RNA quality. J Mol Diagn. 2011;13(6):687-94. https://doi.org/10.1016/j.jmoldx.2011.06.007 PMid:21884819

Li J. Gastric cancer in young adults: A different clinical entity from carcinogenesis to prognosis. Gastroenterol Res Pract. 2020;2020:9512707. https://doi.org/10.1155/2020/9512707

Moore A, Hikri E, Goshen-Lago T, Barkan T, Morgenstern S, Brook E, et al. Young-onset gastric cancer and Epstein-Barr Virus (EBV)-A major player in the pathogenesis? BMC Cancer. 2020;20(1):34. https://doi.org/10.1186/s12885-020-6517-0 PMid:31937281

Shinozaki-Ushiku A, Kunita A, Fukayama M. Update on epstein-barr virus and gastric cancer (review). Int J Oncol. 2015;46(4):1421-34. https://doi.org/10.3892/ijo.2015.2856 PMid:25633561

Ryan JL, Morgan DR, Dominguez RL, Thorne LB, Elmore SH, Mino-Kenudson M, et al. High levels of Epstein-barr virus DNA in latently infected gastric adenocarcinoma. Lab Invest. 2009;89(1):80-90. https://doi.org/10.1038/labinvest.2008.103 PMid:19002111

Tang W, Morgan DR, Meyers MO, Dominguez RL, Martinez E, Kakudo K, et al. Epstein-barr virus infected gastric adenocarcinoma expresses latent and lytic viral transcripts and has a distinct human gene expression profile. Infect Agent Cancer. 2012;7(1):21. https://doi.org/10.1186/1750-9378-7-21 PMid:22929309

Zhang K, Wang H. Cancer genome Atlas pan-cancer analysis project. Zhongguo Fei Ai Za Zhi. 2015;18(4):219-23. https://doi.org/10.3779/j.issn.1009-3419.2015.04.02 PMid:25936886

Agrawal L, Engel KB, Greytak SR, Moore HM. Understanding preanalytical variables and their effects on clinical biomarkers of oncology and immunotherapy. Semin Cancer Biol. 2018;52(Pt 2):26-38. https://doi.org/10.1016/j.semcancer.2017.12.008 PMid:29258857

Shannon-Lowe C, Rowe M. Epstein barr virus entry; kissing and conjugation. Curr Opin Virol. 2014;4:78-84. https://doi.org/10.1016/j.coviro.2013.12.001 PMid:24553068

Caves EA, Butch RM, Cook SA, Wasil LR, Chen C, Di YP, et al. Latent membrane protein 1 is a novel determinant of Epstein-barr virus genome persistence and reactivation. mSphere. 2017;2(6):e00453-17. https://doi.org/10.1128/mSphereDirect.00453-17 PMid:29134204

Tsao SW, Tsang CM, Pang PS, Zhang G, Chen H, Lo KW. The biology of EBV infection in human epithelial cells. Semin Cancer Biol. 2012;22(2):137-43. https://doi.org/10.1016/j.semcancer.2012.02.004 PMid:22497025

Kenney SC, Mertz JE. Regulation of the latent-lytic switch in Epstein-barr virus. Semin Cancer Biol. 2014;26:60-8. https://doi.org/10.1016/j.semcancer.2014.01.002 PMid:24457012

Woellmer A, Hammerschmidt W. Epstein-barr virus and host cell methylation: Regulation of latency, replication and virus reactivation. Curr Opin Virol. 2013;3(3)260-5. https://doi.org/10.1016/j.coviro.2013.03.005 PMid:23567077

Prince S, Keating S, Fielding C, Brennan P, Floettmann E, Rowe M. Latent membrane protein 1 inhibits Epstein-barr virus lytic cycle induction and progress via different mechanisms. J Virol. 2003;77(8):5000-7. https://doi.org/10.1128/jvi.77.8.5000-5007.2003 PMid:12663807

Young LS, Rickinson AB. Epstein-barr virus: 40 years on. Nat Rev Cancer. 2004;4(10):757-68. https://doi.org/10.1038/nrc1452. PMid:15510157

Wang H, Wang J, Zhao B. Correlation of p16 and cyclin D1 expression with the incidence and prognosis of cardiac carcinoma. Oncol Lett. 2019;17(6):4859-64. https://doi.org/10.3892/ol.2019.10189 PMid:31186693

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):787-94. https://doi.org/10.1016/S0002-9440(10)64901-2 PMid:11891177

Osawa T, Chong JM, Sudo M, Sakuma K, Uozaki H, Shibahara J, et al. Reduced expression and promoter methylation of p16 gene in Epstein-Barr virus-associated gastric carcinoma. Jpn J Cancer Res. 2002;93(11):1195-200. https://doi.org/10.1111/j.1349-7006.2002.tb01223.x PMid:12460459

Schneider BG, Gulley ML, Eagan P, Bravo JC, Mera R, Geradts J. Loss of p16/CDKN2A tumor suppressor protein in gastric adenocarcinoma is associated with Epstein-barr virus and anatomic location in the body of the stomach. Hum Pathol. 2000;31(1):45-50. https://doi.org/10.1016/s0046-8177(00)80197-5. PMid:10665912

Downloads

Published

2022-06-03

How to Cite

1.
Samir S, Ahmed HO, Diab TM, Mostafa A, Elmeligy HA, Kamel A, Khalil H. Rate of Epstein-Barr Virus in Gastric Adenocarcinoma in Egyptian Patients in View of the WHO Classification and Correlation with p16 Immunoreactivity. Open Access Maced J Med Sci [Internet]. 2022 Jun. 3 [cited 2026 Oct. 19];10(A):1218-25. Available from: https://oamjms.eu/index.php/mjms/article/view/9700