Abstract
The Epstein Barr virus (EBV) is causally associated to several tumors of epithelial and lymphoid origin. The cancerogenic role in other than B cells has not been proven. This virus has been considered as a target in the effective diagnosis of EBV-associated tumors. For this purpose, molecular biology methods to measure EBV DNA load in the circulation of patients suffering from EBV-related cancers have been recently developed. In this review, we discuss the role of EBV DNA determination, the technical limitations of molecular assays measuring viral load and their impact on the clinical management of patients with EBV-associated tumors arising in the immunocompetent host. Several studies have recently clarified the biological and clinical characteristics of herpesvirus-associated tumors. However, some additional issues must be clarified before introducing viral load determinations into clinical practice. Firstly, since the various EBV-related tumors have different etiopathological and clinical characteristics, the most appropriate biological samples and analytical cut off values must be clearly defined in each group of patients. Secondly, a standardization of the assay, including the definition of the gene segment to be amplified, the use of an international reference for the standard curve and disease-related cut-off values, is strongly required. Thirdly, the interpretation of laboratory data may benefit from an improved design of the studies and obtaining an aggregrate of patients from different institutions, pooling these together, in order to have a sample size that is adequate to reinforce the statistical power of the studies.
Similar content being viewed by others
References
Altman DG, Riley RD (2005) Primer: an evidence-based approach to prognostic markers. Nat Clin Pract Oncol 2:466–472
Anderson J (2006) Epstein-Barr virus and Hodgkin’s lymphoma. Herpes 13:12–16
Au WY, Pang A, Chim CS, Kwong YL (2004) Quantification of circulating Epstein Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer and EBV-positive lymphomas in immunocompetent patients. Blood 104:243–249
Bortolin MT, Pratesi C, Dolcetti R, Bidoli E, Vaccher E, Zanussi S, Tedeschi R, De Paoli P (2006) Clinical value of Epstein-Barr virus DNA levels in peripheral blood samples of Italian patients with undifferentiated carcinoma of nasopharyngeal type. Cancer Lett 233:247–254
Chan AKC, Lo YMD (2002) Circulating EBV DNA as a tumor marker for nasopharyngeal carcinoma. Cancer Biol 12:489–496
Chan KCA, Lo YMD (2006) Clinical applications of plasma Epstein-Barr virus DNA analysis and protocols for the quantitative analysis of the size of circulating Epstein-Barr virus DNA. Meth Mol Biol 336:111–121
Chan KCA, Zhang J, Chan ATC, Lei KIK, Leung SF, Chan LYS, Chow KCK, Lo YMD (2003) Molecular characterization of circulating EBV DNA in the plasma of nasopharyngeal carcinoma and lymphoma patients. Cancer Res 63:2028–2032
Cohen JI (2000) Epstein-Barr virus infection. N Engl J Med 343:481–492
Gallagher A, Armstrong AA, MacKenie J, Shield L, Khan G, Lake A, Proctor S, Taylor P, Clements GB, Jarrett RF (1999) Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV-associated Hodgkin’s disease. Int J Cancer 84:442–448
Gandhi MK, Lambley E, Burrows J, Dua U, Elliott S, Shaw PJ, Prince HM, Wolf M, Clarke K, Underhill C, Mills T, Mollee P, Gill D, Marlton P, Seymour JF, Khanna R (2006) Plasma Epstein-Barr (EBV) DNA is a biomarker for EBV-positive Hodgkin’s lymphoma. Clin Cancer Res 12:460–464
Kimura H, Morita M, Yabuta Y, Kuzushima K, Kato K, Kojima S, Matsuyama T, Morishima T (1999) Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J Clin Microbiol 37:132–136
Le QT, Jones CD, Yau TK, Shirazi HA, Wong PH, Thomas EN, Patterson BK, Lee AW, Zehnder JL (2005) A comparison study of different PCR assays in measuring circulating plasma Epstein-Barr virus DNA levels in patients with nasopharyngeal carcinoma. Clin Cancer Res 11:5700–5707
Leung SF, Chan ATC, Zee B, Ma B, Chan AYS, Johnson PJ, Lo YMD (2003) Pretherapy quantitative measurments of circulating Epstein-Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer 98:288–291
Leung SF, Tam JS, Chan ATC, Zee B, Chan LYS, Huang DP, Van Hasselt A, Johnson PJ, Lo YMD (2004) Improved accuracy of detection of nasopharyngeal carcinoma by combined application of circulating Epstein-Barr virus DNA and anti-Epstein-Barr viral capsid antigen IgA antibody. Clin Chem 50:339–345
Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, Jiang RS (2004) Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. New Engl J Med 350:2461–2470
Lit LCW, Chan KCA, Leung SF, Lei KIK, Chan LYS, Chow KCK, Chan ATC, Lo YMD (2004) Distribution of cell-free and cell-associated Epstein-Barr virus (EBV) DNA in the blood of patients with nasopharyngeal carcinoma and EBV-associated lymphoma. Clin Chem 50:1842–1845
Lo YMD, Chan LYS, Lo KW, Leung SF, Zhang J, Chan ATC, Lee JCK, Hjelm NM, Johnson PJ, Huang AD (1999) Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59:1188–1191
Lo YMD, Leung SF, Chan LYS, Chan ATC, Lo KW, Johnson PJ, Huang DP (2000) Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma. Cancer Res 60:2351–2355
Mbulaiteye SM, Walters M, Engels EA, Bakaki PM, Ndugwa CM, Owor AM, Goedert JJ, Whitby D, Biggar RJ (2006) High levels of Epstein-Barr virus DNA in saliva and peripheral blood from Ugandan mother–child pairs. J Infect Dis 193:422–426
McShane LM, Altan DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC working group on cancer diagnostics (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072
Mc Sween KF, Crawford DH (2003) Epstein-Barr virus—recent advances. Lancet Infect Dis 3:131–140
Mutirangura A, Pornthanakasem W, Theamboonlers A, Sriuranpong V, Lertsanguanschini P, Yenrudi S, Voravud N, Supiyaphun P, Poovorawan Y (1998) Epstein-Barr viral DNA in serum of patients with nasopharyngeal carcinoma. Clin Cancer Res 4:665–669
Niesters HGM (2004) Molecular and diagnostic clinical virology in real time. Clin Microbiol Infect 10:5–11
Pratesi C, Bortolin MT, D’Andrea M, Vaccher E, Barzan L, Bidoli E, Tedeschi R, Zanussi S, De Paoli P (2003) Quantitative plasma/serum EBV DNA load by LMP2A determination in an Italian cohort of NPC patients. J Clin Virol 28:155–164
Sam CK, Brooks LA, Niedobitek G, Young LS, Prasad U, Rickinson AB (1993) Analysis of Epstein-Barr virus infection in nasopharyngeal biopsies from a group at high risk of nasopharyngeal carcinoma. Int J Cancer 53:957–962
Shao JY, Li YH, Gao HY, Wu QL, Cui NJ, Zhang L, Cheng L, Hu LF, Ernberg I, Zeng Yx (2004) Comparison of plasma Epstein-Barr virus (EBV) DNA levels and serum EBV immunoglobulin A/virus capsid antigen antibody titers in patients with nasopharyngeal carcinoma. Cancer 100:1162–1170
Stevens JCS, Pronk I, Middeldorp JM (2001) Toward standardization of Epstein-Barr virus DNA load monitoring: unfractionated whole blood as preferred clinical specimen. J Clin Microbiol 39:1211–1216
Stevens SJC, Verkuijlen AWM, Hariwiyanto B, Harijadi, Palamita DK, Fachiroh J, Adham M, Tan IB, Haryana SM, Middeldorp JM ( 2006) Noninvasive diagnosis of nasopharyngeal carcinoma: nasopharyngeal brushings reveal high Epstein-Barr virus DNA load and carcinoma-specific viral BARF1 mRNA. Int J Cancer 119:608–614
Taylor AL, Marcus R, Bradley JA (2005) Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol 56:155–167
To EWH, Chan KCA, Leung SF, Chan LYS, To KF, Chan ATC, Johnson PJ, Lo YMD (2003) Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res 9:3254–3259
Tong JHM, Tsang RKY, Lo TKW, Kwong J, Chan MWY, Chang AR, Van Hasselt CA, Huang DP, To KF (2002) Quantitative Epstein-Barr virus DNA analysis and detection of gene promoter hypermethylation in nasopharyngeal (NP) brushing samples from patients with NP carcinoma. Clin Cancer Res 8:2612–2619
Twu C, Wang W, Liang W, Jan J, Jiang R, Chao J, Jin Y, Lin C (2007) Comparison of the prognostic impact of serum anti EBV antibody and plasma EBV DNA assays in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 67:130–137
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
De Paoli, P., Pratesi, C. & Bortolin, M.T. The Epstein Barr virus DNA levels as a tumor marker in EBV-associated cancers. J Cancer Res Clin Oncol 133, 809–815 (2007). https://doi.org/10.1007/s00432-007-0281-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-007-0281-2