Prognostic Significance of the Epstein-Barr Virus, p53, Bcl-2, and Survivin in Nasopharyngeal Cancer

Purpose: Nasopharyngeal cancer (NPC) is a malignant epithelial carcinoma which is intimately associated with EBV. The latent presence of EBV affects the function of p53, Bcl-2, and survivin. We thus investigated the relationship between EBV status, p53, Bcl-2, and survivin in biopsy specimens from patients with primary NPC. Experimental Design: Archival formalin-fixed, paraffin-embedded NPC biopsies were evaluated in 80 patients treated with curative radiation from a single institution. The presence of EBV was determined using EBER in situ hybridization, whereas p53, Bcl-2, and survivin were assessed using immunohistochemistry. Results: The majority of NPC specimens in this patient cohort were EBER-positive (64 of 78, or 82%), which in turn, was significantly associated with ethnicity (P = 0.0007), and WHO subtype 2A/2B (P = 0.04). EBER-positive tumors were also associated with p53 (P = 0.002), Bcl-2 (P = 0.04), and nuclear survivin (P = 0.03) expression. Patients with EBER-positive NPC fared better, with a 10-year overall survival of 68% versus 48% for EBER-negative patients (P = 0.03). For nuclear survivin, patients with either low or high nuclear survivin fared worse than patients with intermediate survivin expression (P = 0.05), suggesting that there is an optimal proportion of survivin-expressing cells for best function and clinical outcome. Conclusions: With an extended median follow-up time of 11.4 years, EBV status remains a strong predictor for overall survival in NPC. EBV-positive NPC has strong molecular associations with p53, Bcl-2, and survivin expression. Furthermore, we provide clinical data revealing the potentially dual nature of survivin in predicting clinical outcome.

[1]  R. Gilbert,et al.  Combination Bcl-2 Antisense and Radiation Therapy for Nasopharyngeal Cancer , 2005, Clinical Cancer Research.

[2]  P. Morin,et al.  Claudin proteins in human cancer: promising new targets for diagnosis and therapy. , 2005, Cancer research.

[3]  Kathryn A. O’Donnell,et al.  The great MYC escape in tumorigenesis. , 2005, Cancer cell.

[4]  P. Pandolfi,et al.  Role of nucleophosmin in embryonic development and tumorigenesis , 2005, Nature.

[5]  C. Meijer,et al.  Absence of caspase 3 activation in neoplastic cells of nasopharyngeal carcinoma biopsies predicts rapid fatal outcome , 2005, Modern Pathology.

[6]  F. Tang,et al.  Epstein-Barr virus LMP1 initiates cell proliferation and apoptosis inhibition via regulating expression of Survivin in nasopharyngeal carcinoma. , 2005, Experimental oncology.

[7]  D. Tan,et al.  Nuclear or cytoplasmic expression of survivin: What is the significance? , 2005, International journal of cancer.

[8]  C. Arrowsmith,et al.  Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. , 2005, Molecular cell.

[9]  S. Leung,et al.  Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. , 2005, International journal of radiation oncology, biology, physics.

[10]  L. Young,et al.  Epstein–Barr virus: 40 years on , 2004, Nature Reviews Cancer.

[11]  J. Grandis,et al.  Mutation of p53 in head and neck squamous cell carcinoma correlates with Bcl‐2 expression and increased susceptibility to cisplatin‐induced apoptosis , 2004, Head & neck.

[12]  R. Gilbert,et al.  Potential utility of BimS as a novel apoptotic therapeutic molecule. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  John Calvin Reed,et al.  An IAP-IAP Complex Inhibits Apoptosis* , 2004, Journal of Biological Chemistry.

[14]  S. Sen,et al.  Combined evaluation of expression of telomerase, survivin, and anti‐apoptotic bcl‐2 family members in relation to loss of differentiation and apoptosis in human head and neck cancers , 2004, Head & neck.

[15]  J Silvio Gutkind,et al.  Global Gene Expression Profile of Nasopharyngeal Carcinoma by Laser Capture Microdissection and Complementary DNA Microarrays , 2004, Clinical Cancer Research.

[16]  Kwok Wai Lo,et al.  Focus on nasopharyngeal carcinoma. , 2004, Cancer cell.

[17]  Muyang Li,et al.  A dynamic role of HAUSP in the p53-Mdm2 pathway. , 2004, Molecular cell.

[18]  F. Bosch,et al.  Nuclear survivin expression in mantle cell lymphoma is associated with cell proliferation and survival. , 2004, The American journal of pathology.

[19]  N. Perkins,et al.  NF-κB: tumor promoter or suppressor? , 2004 .

[20]  H. Nagawa,et al.  Survivin expression in ovarian carcinoma: correlation with apoptotic markers and prognosis , 2004, Modern Pathology.

[21]  P. Warde,et al.  Limitation of conventional two dimensional radiation therapy planning in nasopharyngeal carcinoma. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[22]  C. Cohen,et al.  Survivin Expression in Ovarian Carcinoma: Correlation with Apoptotic Markers and Prognosis , 2003, Modern Pathology.

[23]  R. Gilbert,et al.  Loss of p16 expression has prognostic significance in human nasopharyngeal carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  K. Shroyer,et al.  Survivin expression in human osteosarcoma is a marker for survival. , 2003, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[25]  L. O’Driscoll,et al.  Prognostic importance of survivin in breast cancer , 2003, British Journal of Cancer.

[26]  H. Stein,et al.  Prognostic value of nuclear survivin expression in oesophageal squamous cell carcinoma , 2003, British Journal of Cancer.

[27]  N. Raab-Traub.  Epstein-Barr virus in the pathogenesis of NPC. , 2002, Seminars in cancer biology.

[28]  P. Warde,et al.  Radiotherapy alone in patients with advanced nasopharyngeal cancer: comparison with an intergroup study. Is combined modality treatment really necessary? , 2002, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[29]  D. McConkey,et al.  Comparative study of various biological parameters, including expression of survivin, between primary and metastatic human colonic adenocarcinomas. , 2002, Anticancer research.

[30]  P. Zubizarreta,et al.  Epstein Barr virus associated pediatric nasopharyngeal carcinoma: its correlation with p53 and bcl-2 expression. , 2002, Medical and pediatric oncology.

[31]  P. Warde,et al.  Molecular pathology parameters in human nasopharyngeal carcinoma , 2002, Cancer.

[32]  B. Boman,et al.  Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. , 2001, Cancer research.

[33]  P. Xia,et al.  Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. , 2001, International journal of radiation oncology, biology, physics.

[34]  M. Chang,et al.  Association of p53 and BCL‐2 expression with Epstein‐Barr virus infection in the cancers of head and neck , 2001, Head & neck.

[35]  S. Moriyama,et al.  Expression of survivin in esophageal cancer: Correlation with the prognosis and response to chemotherapy , 2001, International journal of cancer.

[36]  S. Maeda,et al.  Co-expression of p53 and bcl-2 may correlate to the presence of epstein-barr virus genome and the expression of proliferating cell nuclear antigen in nasopharyngeal carcinoma. , 2000, Cancer letters.

[37]  C. Lin,et al.  Epstein-barr virus nuclear antigen 2 retards cell growth, induces p21(WAF1) expression, and modulates p53 activity post-translationally. , 2000, Journal of molecular biology.

[38]  P. Hall,et al.  The p53 molecule and its prognostic role in squamous cell carcinomas of the head and neck. , 2000, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[39]  B. Czerniak,et al.  Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer , 1999, Oncogene.

[40]  J. Marks,et al.  The national cancer data base report on the relationship of race and national origin to the histology of nasopharyngeal carcinoma , 1998, Cancer.

[41]  S. Groshen,et al.  Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. , 1998, Cancer research.

[42]  M. Gulley,et al.  Epstein-Barr virus infection is associated with p53 accumulation in nasopharyngeal carcinoma. , 1998, Human pathology.

[43]  T. Taniguchi,et al.  Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity , 1997, Oncogene.

[44]  W. Lee,et al.  Analysis of bcl-2 expression in normal, inflamed, dysplastic nasopharyngeal epithelia, and nasopharyngeal carcinoma: association with p53 expression. , 1997, Human pathology.

[45]  Q. Zhang,et al.  Functional and physical interaction between p53 and BZLF1: implications for Epstein-Barr virus latency , 1994, Molecular and cellular biology.

[46]  P. Barber,et al.  P53 overexpression and Epstein‐Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas , 1993, The Journal of pathology.

[47]  L. Szekely,et al.  EBNA-5, an Epstein-Barr virus-encoded nuclear antigen, binds to the retinoblastoma and p53 proteins. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[48]  T. Tursz,et al.  Alterations of the p53 gene in nasopharyngeal carcinoma , 1992, Journal of virology.

[49]  S W Lagakos,et al.  Nonparametric estimation of lifetime and disease onset distributions from incomplete observations. , 1982, Biometrics.

[50]  Robert N. Hughes,et al.  Cancer: Principles and Practice of Oncology , 2005 .

[51]  R. Gilbert,et al.  Loss of p 16 Expression Has Prognostic Significance in Human Nasopharyngeal Carcinoma 1 , 2003 .

[52]  D. Altieri.  Validating survivin as a cancer therapeutic target , 2003, Nature Reviews Cancer.