p16 overexpression as a predictor of survival in ocular surface squamous neoplasia.

Aims To evaluate the expression and methylation status of the p16(INK4a) gene in early and advanced American Joint Committee on Cancer (AJCC) stages of ocular surface squamous neoplasia (OSSN) and to correlate its association with clinicopathological features and survival. Methods Sixty-four (35 early and 29 advanced AJCC stage) patients with OSSN formed part of this study and were followed up for 36-58 (mean 483.6) months. Immunohistochemical expression of the p16(INK4a) protein and methylation status of the p16(INK4a) gene were determined by methylation-specific PCR. Results Overexpression of p16(INK4a) was observed in 18/64 (28%) and hypermethylation in 35/64 (54.7%) OSSN cases. A gradual significant increase in the expression of p16(INK4a) (0%-48%, P=0.03) and decrease in its methylation (75%-16%, P=0.001) was observed with disease progression from early to advanced tumour stage. Overexpression of p16(INK4a) was significantly associated with palpebral location and diffuse growth pattern in both early and advanced T stage. Hypermethylation of p16(INK4a) was significantly associated with history of longer sunlight exposure in both early and advanced T stage of OSSN cases. In advanced T stage, p16(INK4a) overexpression was associated with reduced disease-free survival (P=0.02) and poor prognosis (HR, 0.2; P=0.03). Conclusions OSSN patients presenting at an advanced AJCC stage with p16(INK4a) overexpression may require more aggressive treatment. Epigenetic inactivation of the p16(INK4a) gene due to sunlight exposure could be responsible for pathogenesis of OSSN.