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Loss of p16 Expression Has Prognostic Significance in Human Nasopharyngeal Carcinoma¹

Departments of Otolaryngology and Surgical Oncology [A. A. M., J. I., D. B., R. G., P. G.], Radiation Oncology [B. O., D. P., B. C., J. W., P. W., F-F. L.], Molecular and Cellular Biology [A. A. M., S. K-R.], Experimental Therapeutics [W. S., A. L., F-F. L.], Pathology [C. M., J. H., S. K-R.], Biostatistics [M. P.], Princess Margaret Hospital/Ontario Cancer Institute, Toronto M5G 2M9, and University Health Network, Departments of Otolaryngology and Surgical Oncology [J. I., D. B., R. G., P. G., S. K-R.], Medical Biophysics [W. S., A. L., F-F. L., S. K-R.], Pathobiology and Laboratory Medicine [C. M., S. K-R.], and Radiation Oncology [B. O., D. P., B. C., J. W., P. W., F-F. L.], University of Toronto, Toronto, Ontario, Canada

Purpose: p16 is an important inhibitor of cell cycle progression; absence of p16 can thus result in increased cellular proliferation. In nasopharyngeal carcinoma (NPC), absence of p16 has been reported in association with presence of the EBV and pRb. We therefore examined p16, pRb, and EBV-encoded RNA (EBER) expression in biopsy specimens from 84 patients with newly diagnosed NPC, who were treated primarily with curative radiation therapy. Our objective was to determine whether there was a correlation between these parameters and clinical outcome in NPC.

Experimental Design: Sections were cut from archival formalin-fixed, paraffin-embedded tumor blocks from NPC patients. p16 and pRb expression were determined using polyclonal and monoclonal antibodies, respectively. The presence of EBV was determined by in situ hybridization for EBER. The percentage of positively staining tumor nuclei was scored for p16 or pRb immunoreactivity. Relative intensity and proportion of cells with EBER signals were also documented.

Results: p16 expression was reduced (≤5% positive immunoexpression) in 59 of 84 (70%) NPC samples; in contrast, pRb was observed in all (100%) tumors. EBER signals were detected in 67 of 83 (81%) NPC specimens. There was a weak correlation between EBER presence and loss of p16 (P = 0.1). Using a Cox regression model controlling for known prognostic parameters, such as age, weight loss, and tumor stage, complete absence of p16 expression (0%, i.e., no immunostaining identified throughout the specimen) was associated with an inferior overall survival rate (P = 0.022). In addition, EBER-positive NPC was strongly associated with improved overall survival (P = 0.005) as reported previously (Shi et al., Cancer, 94: 1997, 2002).

Conclusion: These results provide the first evidence suggesting that inactivation of p16 appears to be a significant predictor for poor overall survival in NPC. Given that reduced p16 expression is observed in the majority of patients with NPC, this indicates that therapeutic strategies targeting the p16 pathway may be a biologically rational approach for NPC. The favorable prognostic value of EBER suggests that future clinical trials with NPC should consider stratifying for EBER status.

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