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p14^ARF Protein Expression Is a Predictor of Both Relapse and Survival in Squamous Cell Carcinoma of the Anterior Tongue

Authors' Affiliations: ¹ Cancer Research Program and ² Bone and Mineral Research Program, Garvan Institute of Medical Research; ³ Department of ENT Surgery, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia and ⁴ Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia

Requests for reprints: Robert L. Sutherland, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. Phone: 612-9295-8322; Fax: 612-9295-8321; E-mail: r.sutherland{at}garvan.org.au.

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, p16^INK4A and p14^ARF. This study addressed the role of p14^ARF as a potential prognostic marker in this disease.

Experimental Design: p14^ARF 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 p14^ARF (p16^INK4A, p53, pRb, p21^WAF1/CIP1, E2F-1).

Results: On multivariate analysis, p14^ARF positivity (nucleolar p14^ARF staining and/or nuclear p14^ARF 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 p14^ARF positivity was cosegregated with positive (1%) p16^INK4A 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 p14^ARF protein predicts for improved DFS and OS independent of established prognostic markers.

Key Words: p16^INK4A • head and neck cancer • E2F-1 • prognostic marker • p53

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