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Overexpression of E2F-1 Is Associated with Increased Disease-free Survival in Squamous Cell Carcinoma of the Anterior Tongue¹

Cancer Research Program [R. A. K., J. G. K., E. A. M., S. M. H., R. L. S.] and Bone and Mineral Research Program [T. V. N.], Garvan Institute of Medical Research, Darlinghurst, NSW 2010; Department of Otorhinolaryngology Surgery, St. Vincent’s Hospital, Darlinghurst, NSW 2010 [R. J. B., I. E. C.]; and Institute of Clinical Pathology and Medical Research, Westmead, NSW 2145 [J. G. K.], Australia

Purpose: Overexpression of E2F-1 is associated with increased invasiveness in head and neck squamous cell carcinoma cell lines in vitro, but its significance in vivo is unknown. This study sought to determine the relationship between E2F-1 and retinoblastoma protein (pRb) expression and disease outcome in squamous cell carcinoma (SCC) of the anterior tongue.

Experimental Design: pRb and E2F-1 protein expression was assessed by immunohistochemistry in a cohort of 145 patients with SCC of the anterior tongue. The outcomes examined were time to disease recurrence or death. The relationships between E2F-1 or pRb expression and outcome were assessed by univariate and multivariate Cox’s proportional hazards model, with or without clinicopathological covariates, including nodal status, disease stage, treatment status, and molecular markers (cyclin D1, p16^INK4A, and Ki-67) previously measured in this cohort.

Results: On univariate analysis, increased expression of E2F-1 (>35% of positive-stained nuclei) was associated with increased disease-free survival (DFS; hazard ratio [HR]: 0.35; P = 0.04) and increased overall survival (OS; HR: 0.33; P = 0.06). Decreased expression of pRb (<50% positive nuclei) was associated with increased DFS (HR: 1.81; P = 0.06) but not with OS (P = 0.11). However, when considered simultaneously with other significant factors, i.e. lymph node status, p16^INK4A protein expression, and histopathological grade, in the multivariate Cox’s proportional hazards model, the additional contributions of E2F-1 and/or pRb expression to DFS and OS were not statistically significant.

Conclusions: These data demonstrate that in patients with SCC of the tongue, overexpression of E2F-1 is associated with increased DFS and OS. However, this association is not independent of lymph node status, tumor grade, and p16^INK4A expression. Among the cell cycle-regulatory molecules studied, p16^INK4A expression is the most predictive molecular marker of disease outcome.

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