Abstract A03: Epigenetic alterations of stratifin in ocular surface squamous neoplasia: Pathogenesis and prognosis

Abstract

Abstract Purpose: Ocular Surface Squamous neoplasia (OSSN) is the most common tumor of conjunctival epithelium associated with risk of permanent visual impairment. It includes conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC).Of the multifactorial etiopathogenesis of OSSN, ultraviolet irradiation has been reported as a major risk factor in the pathogenesis of OSSN. Sunlight induced p53 mutations are known to contribute towards increased risk of OSSN. Stratifin (14-3-3σ)/HEM (human epithelial marker) is a p53 mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status and expression of mutant p53 in OSSN was studied. The significance of Stratifin and p53 in the pathogenesis and prognosis of ocular surface squamous neoplasia (OSSN) patients was also evaluated. Methods: Sixty-four histopathologically confirmed OSSN cases (44 SCC and 20 CIN) were included in this study. AJCC TNM staging was performed 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 and p53. Results: Loss of Stratifin immunoexpression was observed in 75% (48/64) and 48% (31/64) cases showed mutant p53 expression. Hypermethylation of Stratifin promoter was seen in 63% (40/64) OSSN cases. Of the 48 cases with loss of Stratifin expression, promoter hypermethylation was seen in 35% (17/48), mutant p53 expression in 10% (5/48) and both promoter hypermethylation and mutant p53 expression in 58% (23/48) cases. These results indicate that both hypermethylation of Stratifin and mutant p53 expression are associated with loss of Stratifin in OSSN cases. On statistical analysis, Stratifin loss was significantly associated with tumor size >2cm, T3 and T4 category, poor histopathological differentiation of SCC and reduced disease free survival (P 0.05). Cox analysis showed Stratifin to be an independent prognostic marker for OSSN (p =0.03) patients. Mutant p53 expression was associated with history of longer sunlight exposure in 56% cases. No significant correlation was observed between mutant p53 expression and other clinicopathological feature or clinical outcome. Conclusions: Our results indicate that loss of Stratifin is a key event in the pathogenesis of OSSN. Presence of both aberrant methylation of Stratifin and mutant p53 expression implicates involvement of p53-Stratifin mediated signalling pathway in the pathogenesis of OSSN. Stratifin loss may also prove to be a useful biomarker for identifying high risk OSSN patients. Citation Format: Sheetal Chauhan, Seema Sen, Anjana Sharma, Shyam S. Chauhan, Seema Kashyap, Radhika Tandon, Neelam Pushker, M Vanathi. Epigenetic alterations of stratifin in ocular surface squamous neoplasia: Pathogenesis and prognosis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A03.