Stratifin- A novel biomarker in the prognosis of Ocular Surface Squamous Neoplasia patients

Abstract

Purpose: Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53 mediated inhibitor of cell cycle progression; it has been shown to be a target of epigenetic deregulation in many carcinomas. In the present study, the association of Stratifin expression with it’s promoter methylation status and mutant p53 expression was undertaken. The prognostic significance of Stratifin in ocular surface squamous neoplasia (OSSN) patients was also evaluated.

Methods: Sixty-four histopathologically confirmed OSSN cases (44 squamous cell carcinomas and 20 conjunctival intraepithelial neoplasias) were included in this study. AJCC TNM staging was done and patients were followed up for 32 months. Immunohistochemical expression of Stratifin (clone-ab14123) and mutant p53 (clone-DO7) protein was evaluated; methylation status of Stratifin was determined by methylation specific PCR using specific primers. Kaplan-Meier survival and Cox regression analysis was done to assess the prognostic significance of Stratifin.

Results: Loss of Stratifin immunoexpression was observed in 75% (48/64) and its promoter hypermethylation in 63% (40/64) OSSN cases. Loss of Stratifin expression significantly correlated with it’s promoter hypermethylation (P=<0.0001). Expression of mutant p53 protein was seen in 48% (31/64) cases and this inversely correlated with Stratifin immunoexpression (P=0.009). Both loss of Stratifin immunoexpression and it’s promoter hypermethylation, were significantly associated with tumor size 2cm, T3 and T4 category and reduced disease free survival (P 0.05). Cox analysis showed Stratifin to be independent prognostic marker for OSSN (p =0.03).

Conclusions: Our results indicate that loss of Stratifin expression occurs in OSSN and is caused by aberrant DNA methylation. Relationship between mutant p53 and Stratifin suggests that abnormalities in p53-stratifin pathway could play an important role in the pathogenesis of OSSN. Loss of Stratifin immunoexpression could prove to be a useful biomarker to identify high risk OSSN patients.

Keywords: 554 immunohistochemistry • 744 tumors