Skip to main content

Biomarkers in Nasopharyngeal Carcinoma and Ionizing Radiation

  • Reference work entry
Biomarkers in Cancer

Abstract

Cancer of the nasopharynx is an epithelial cancer developed in the retro-nasal area in the nasal cavity. Nasopharyngeal carcinoma (NPC) is prevalent in the endemic regions including Southern China and Southeast Asia. The primary tumor of NPC is small and usually causes no symptoms. Patients often present with bilateral glands enlargement and local/regional lymph node metastasis leading to poor prognosis and local control rate. Therefore, there is a desperate need to develop early diagnosis method to improve the treatment outcome. Detection of EBV-derived biomarkers in tissues and EBV DNA in the peripheral blood of NPC patients opens up the possibility to monitor the disease using molecular markers with high sensitivity. Among the biomarkers in tissue, in situ hybridization for EBER remains to be the most efficient and reliable way because EBER is the most abundantly expressed viral transcript. In addition to diagnosis value, EBER, EBNA1, and LMP1 levels in tissue after radiation therapy could serve as biomarkers to evaluate response to radiotherapy. In light of the detection of EBV DNA in plasma, serum, nasal brush, and saliva, EBV DNA is particularly useful for periodic monitoring of NPC patients. A systematic review has revealed that circulating EBV DNA could be applied as noninvasive diagnostic biomarker for NPC. Moreover, the close association of circulating EBV DNA with the clinical outcomes of treatment provided new tool to predict the treatment outcome. Nevertheless, circulating EBV DNA was not detectable in all the undifferentiated NPC patients, and EBV latent infection was not associated with WHO-1 NPC, which limits the utility of EBV DNA. Further studies are warranted to identify complementary biomarkers originating from the human cancer cells to overcome the limitation of EBV-based biomarkers in NPC screening and monitoring treatment outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

Abbreviations

CT:

Computerized Tomography

EA:

Early Antigen

EBER:

Epstein–Barr-Encoded RNA

EBNA:

Epstein–Barr Nuclear Antigen

EBV:

Epstein–Barr Virus

IARC:

International Agency for Research on Cancer

IM:

Infectious Mononucleosis

LMP:

Latent Membrane Protein

MHC:

Major Histocompatibility Complex

MRI:

Magnetic Resonance Imaging

NPC:

Nasopharyngeal Carcinoma

VCA:

Viral Capsid Antigen

WHO:

World Health Organization

References

  • Abdulkarim B, Sabri S, Zelenika D, et al. Antiviral agent cidofovir decreases Epstein-Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies. Oncogene. 2003;22:2260–71.

    Article  CAS  PubMed  Google Scholar 

  • Adham M, Greijer AE, Verkuijlen SA, et al. Epstein-Barr virus DNA load in nasopharyngeal brushings and whole blood in nasopharyngeal carcinoma patients before and after treatment. Clin Cancer Res. 2013;19:2175–86.

    Article  CAS  PubMed  Google Scholar 

  • Brennan B. Nasopharyngeal carcinoma. Orphanet J Rare Dis. 2006;1:23.

    Article  PubMed  PubMed Central  Google Scholar 

  • Busson P, Keryer C, Ooka T, et al. EBV-associated nasopharyngeal carcinomas: from epidemiology to virus-targeting strategies. Trends Microbiol. 2004;12:356–60.

    Article  CAS  PubMed  Google Scholar 

  • Chan MK, Huang DP. The value of cytologic examination for nasopharyngeal carcinoma. Ear Nose Throat J. 1990;69:268–71.

    CAS  PubMed  Google Scholar 

  • Chan KC, Lo YM. Circulating EBV DNA as a tumor marker for nasopharyngeal carcinoma. Semin Cancer Biol. 2002;12:489–96.

    Article  CAS  PubMed  Google Scholar 

  • Chan AT, Lo YM, Zee B, et al. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst. 2002;94:1614–19.

    Article  CAS  PubMed  Google Scholar 

  • Chan KC, Hung EC, Woo JK, et al. Early detection of nasopharyngeal carcinoma by plasma Epstein-Barr virus DNA analysis in a surveillance program. Cancer. 2013;119:1838–44.

    Article  CAS  PubMed  Google Scholar 

  • Chang C, Middeldorp J, Yu KJ, et al. Characterization of ELISA detection of broad-spectrum anti-Epstein-Barr virus antibodies associated with nasopharyngeal carcinoma. J Med Virol. 2013;85:524–9.

    Article  CAS  PubMed  Google Scholar 

  • Chien YC, Chen JY, Liu MY, et al. Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med. 2001;345:1877–82.

    Article  CAS  PubMed  Google Scholar 

  • Clemens MJ. The small RNAs of Epstein-Barr virus. Mol Biol Rep. 1993;17:81–92.

    Article  CAS  PubMed  Google Scholar 

  • Dawson CW, Port RJ, Young LS. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol. 2012;22:144–53.

    Article  CAS  PubMed  Google Scholar 

  • de Vathaire F, Sancho-Garnier H, de Thé H, et al. Prognostic value of EBV markers in the clinical management of nasopharyngeal carcinoma (NPC): a multicenter follow-up study. Int J Cancer. 1988;42:176–81.

    Article  Google Scholar 

  • Fåhraeus R, Fu HL, Ernberg I, et al. Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma. Int J Cancer. 1988;42:329–38.

    Article  PubMed  Google Scholar 

  • Fan SQ, Ma J, Zhou J, Xiong W, et al. Differential expression of Epstein-Barr virus-encoded RNA and several tumor-related genes in various types of nasopharyngeal epithelial lesions and nasopharyngeal carcinoma using tissue microarray analysis. Hum Pathol. 2006;37:593–605.

    Article  CAS  PubMed  Google Scholar 

  • Gilligan K, Rajadurai P, Resnick L, et al. Epstein-Barr virus small nuclear RNAs are not expressed in permissively infected cells in AIDS-associated leukoplakia. Proc Natl Acad Sci U S A. 1990;87:8790–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gulley ML. Molecular diagnosis of Epstein-Barr virus-related diseases. J Mol Diagn. 2001;3:1–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus-related disease. J Mol Diagn. 2008;10:279–92.

    Article  PubMed  PubMed Central  Google Scholar 

  • Han BL, Xu XY, Zhang CZ, et al. Systematic review on Epstein-Barr virus (EBV) DNA in diagnosis of nasopharyngeal carcinoma in Asian populations. Asian Pac J Cancer Prev. 2012;13:2577–81.

    Article  PubMed  Google Scholar 

  • Hao SP, Tsang NM, Chang KP. Monitoring tumor recurrence with nasopharyngeal swab and latent membrane protein-1 and epstein-barr nuclear antigen-1 gene detection in treated patients with nasopharyngeal carcinoma. Laryngoscope. 2004;114:2027–30.

    Article  CAS  PubMed  Google Scholar 

  • Henle G, Henle W. Epstein-Barr virus-specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma. Int J Cancer. 1976;17:1–7.

    Article  CAS  PubMed  Google Scholar 

  • Jayasurya A, Bay BH, Yap WM, et al. Lymphocytic infiltration in undifferentiated nasopharyngeal cancer. Arch Otolaryngol Head Neck Surg. 2000;126:1329–32.

    Article  CAS  PubMed  Google Scholar 

  • Kaye KM, Izumi KM, Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993;90:9150–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kieff E. Epstein-Barr virus and its replication. In: Fields B, Knipes D, Howley PM, et al., editors. Fields virology. 3rd ed. Philadelphia: Lippincott-Raven; 1996. p. 2343–95.

    Google Scholar 

  • Kottaridis SD, Panotopoulou E, Diamantis I, et al. Nasopharyngeal carcinoma: Epstein-Barr Virus significance. Anticancer Res. 1996;16:785–9.

    CAS  PubMed  Google Scholar 

  • Kutok JL, Wang F. Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol. 2006;1:375–404.

    Article  CAS  PubMed  Google Scholar 

  • Lee AW, Lin JC, Ng WT. Current management of nasopharyngeal cancer. Semin Radiat Oncol. 2012;22:233–44.

    Article  PubMed  Google Scholar 

  • Levitskaya J, Coram M, Levitsky V, et al. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature. 1995;375:685–8.

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Fang Z, Liu L, et al. Detection of Epstein-Barr virus DNA in serum or plasma for nasopharyngeal cancer: a meta-analysis. Genet Test Mol Biomarkers. 2011;15:495–502.

    Article  CAS  PubMed  Google Scholar 

  • Lo YM, Leung SF, Chan LY, et al. Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma. Cancer Res. 2000;60:2351–5.

    CAS  PubMed  Google Scholar 

  • Loh LE, Chee TS, John AB. The anatomy of the Fossa of Rosenmuller – its possible influence on the detection of occult nasopharyngeal carcinoma. Singapore Med J. 1991;32:154–5.

    CAS  PubMed  Google Scholar 

  • Lu H, Peng L, Yuan X, et al. Concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: a treatment paradigm also applicable to patients in Southeast Asia. Cancer Treat Rev. 2009;35:345–53.

    Article  PubMed  Google Scholar 

  • Mei YP, Zhou JM, Wang Y, et al. Silencing of LMP1 induces cell cycle arrest and enhances chemosensitivity through inhibition of AKT signaling pathway in EBV-positive nasopharyngeal carcinoma cells. Cell Cycle. 2007;6:1379–85.

    Article  CAS  PubMed  Google Scholar 

  • Nicholls JM, Chua D, Chiu PM, et al. The detection of clinically occult nasopharyngeal carcinoma in patients following radiotherapy – an analysis of 69 patients. J Laryngol Otol. 1996;110:496–9.

    Article  CAS  PubMed  Google Scholar 

  • Pathmanathan R, Prasad U, Sadler R, et al. Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med. 1995;333:693–8.

    Article  CAS  PubMed  Google Scholar 

  • Pickard A, Chen CJ, Diehl SR, et al. Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan. Int J Cancer. 2004;111:117–23.

    Article  CAS  PubMed  Google Scholar 

  • Pow EH, Law MY, Tsang PC, et al. Salivary Epstein-Barr virus DNA level in patients with nasopharyngeal carcinoma following radiotherapy. Oral Oncol. 2011;47:879–82.

    Article  CAS  PubMed  Google Scholar 

  • Raab-Traub N. Epstein-Barr virus in the pathogenesis of NPC. Semin Cancer Biol. 2002;12:431–41.

    Article  CAS  PubMed  Google Scholar 

  • Regaud C. Lympho-epitheliome de l’hypopharynx traité par la roentgenthérapie. Bull Soc Franc Otorhinolaryngol. 1921;34:209–14.

    Google Scholar 

  • Roh JL. Transpalatal endoscopic resection of residual nasopharyngeal carcinoma after sequential chemoradiotherapy. J Laryngol Otol. 2004;118:951–4.

    Article  PubMed  Google Scholar 

  • Rowe M, Rowe DT, Gregory CD, et al. Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt’s lymphoma cells. EMBO J. 1987;6:2743–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sam CK, Brooks LA, Niedobitek G, et al. Analysis of Epstein-Barr virus infection in nasopharyngeal biopsies from a group at high risk of nasopharyngeal carcinoma. Int J Cancer. 1993;53:957–62.

    Article  CAS  PubMed  Google Scholar 

  • Schmincke A. Über lymphoepitheliale Geschwülste. Beitr Pathol Anat. 1921;68:161–70.

    Google Scholar 

  • Sham JS, Wei WI, Kwan WH, et al. Fiberoptic endoscopic examination and biopsy in determining the extent of nasopharyngeal carcinoma. Cancer. 1989;64:1838–42.

    Article  CAS  PubMed  Google Scholar 

  • Sham JS, Wei WI, Zong YS, et al. Detection of subclinical nasopharyngeal carcinoma by fibreoptic endoscopy and multiple biopsy. Lancet. 1990;335:371–4.

    Article  CAS  PubMed  Google Scholar 

  • Shao JY, Li YH, Gao HY, et al. 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. 2004a;100:1162–70.

    Article  CAS  PubMed  Google Scholar 

  • Shao JY, Zhang Y, Li YH, et al. Comparison of Epstein-Barr virus DNA level in plasma, peripheral blood cell and tumor tissue in nasopharyngeal carcinoma. Anticancer Res. 2004b;24:4059–66.

    CAS  PubMed  Google Scholar 

  • Shi W, Pataki I, MacMillan C, et al. Molecular pathology parameters in human nasopharyngeal carcinoma. Cancer. 2002;94:1997–2006.

    Article  CAS  PubMed  Google Scholar 

  • Shibata D, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol. 1992;140:769–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shimakage M, Ikegami N, Chatani M, et al. Serological follow-up study on the antibody levels to Epstein-Barr virus-determined nuclear antigen (EBNA) patients with nasopharyngeal carcinoma (NPC) after radiation therapy. Biken J. 1987;30:45–51.

    CAS  PubMed  Google Scholar 

  • Shotelersuk K, Khorprasert C, Sakdikul S, et al. Epstein-Barr virus DNA in serum/plasma as a tumor marker for nasopharyngeal cancer. Clin Cancer Res. 2000;6:1046–51.

    CAS  PubMed  Google Scholar 

  • To EW, Chan KC, Leung SF, et al. Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res. 2003;9:3254–9.

    CAS  PubMed  Google Scholar 

  • Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43:831–40.

    Article  CAS  PubMed  Google Scholar 

  • Wee J, Tan EH, Tai BC, et al. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol. 2005;23:6730–8.

    Article  CAS  PubMed  Google Scholar 

  • Wei WI, Sham JS. Nasopharyngeal carcinoma. Lancet. 2005;365:2041–54.

    Article  PubMed  Google Scholar 

  • Westhoff Smith D, Sugden B. Potential cellular functions of Epstein-Barr Nuclear Antigen 1 (EBNA1) of Epstein-Barr Virus. Viruses. 2013;5:226–40.

    Article  PubMed  Google Scholar 

  • Yang X, Goldstein AM, Chen CJ, et al. Distribution of Epstein-Barr viral load in serum of individuals from nasopharyngeal carcinoma high-risk families in Taiwan. Int J Cancer. 2006;118:780–4.

    Article  CAS  PubMed  Google Scholar 

  • Yip KW, Shi W, Pintilie M, et al. Prognostic significance of the Epstein-Barr virus, p53, Bcl-2, and survivin in nasopharyngeal cancer. Clin Cancer Res. 2006;12:5726–32.

    Article  CAS  PubMed  Google Scholar 

  • Yip WK, Abdullah MA, Yusoff SM, Seow HF. Increase in tumour-infiltrating lymphocytes with regulatory T cell immunophenotypes and reduced zeta-chain expression in nasopharyngeal carcinoma patients. Clin Exp Immunol. 2009;155:412–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004;4:757–68.

    Article  CAS  PubMed  Google Scholar 

  • Zeng Y. Seroepidemiological studies on nasopharyngeal carcinoma in China. Adv Cancer Res. 1985;44:121–38.

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Wang Y, Zeng S, et al. LMP1 expression is positively associated with metastasis of nasopharyngeal carcinoma: evidence from a meta-analysis. J Clin Pathol. 2012;65:41–5.

    Article  CAS  PubMed  Google Scholar 

  • zur Hausen H, Schulte-Holthausen H, Klein G, et al. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature. 1970;228:1056–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Thian-Sze Wong .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Wong, TS., Gao, W., Chan, J.YW. (2015). Biomarkers in Nasopharyngeal Carcinoma and Ionizing Radiation. In: Preedy, V., Patel, V. (eds) Biomarkers in Cancer. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7681-4_39

Download citation

Publish with us

Policies and ethics