p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue

Abstract

Purpose: The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16INK4A and p14ARF. This study addressed the role of p14ARF as a potential prognostic marker in this disease. Experimental Design: p14ARF protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox's proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with P14ARF (p16INK4A, p53, pRb, p21 WAF1/CIP1, E2F-1). Results: On multivariate analysis, p14 ARF positivity (nucleolar p14ARF staining and/or nuclear p14ARF staining in ≥ 30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14ARF positivity was cosegregated with positive (≥ 1%) p16INK4A staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14 ARF negative and p53 positive (> 50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed. Conclusions: These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14ARF protein predicts for improved DFS and OS independent of established prognostic markers. © 2005 American Association for Cancer Research.