p16^INK4a overexpression as a predictor of survival in ocular surface squamous neoplasia.

Abstract

To evaluate the expression and methylation status of the <i>p16</i>^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. 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 48±3.6) months. Immunohistochemical expression of the p16^INK4a protein and methylation status of the <i>p16</i>^INK4a gene were determined by methylation-specific PCR. 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). OSSN patients presenting at an advanced AJCC stage with p16^INK4a overexpression may require more aggressive treatment. Epigenetic inactivation of the <i>p16^INK4a</i> gene due to sunlight exposure could be responsible for pathogenesis of OSSN.