Prognostic role of promoter hypermethylation of death-associated protein (DAP) kinase and p16 genes in early-stage non-small cell lung cancer

Abstract

7216 Background: Promoter hypermethylation is an epigenetic mechanism of gene silencing commonly observed in malignancies. Prior studies suggest that hypermethylation of DAP kinase and p16, genes involved in apoptosis and cell cycle regulation, respectively, are associated with poorer survival in NSCLC patients. In this study we investigate the prognostic role of DAP kinase and p16 promoter hypermethylation in a large cohort of early-stage NSCLC patients. Methods: Pathologic stage I and II NSCLC patients who underwent complete surgical resection between 1/97 and 12/01 at our institution and did not receive adjuvant therapy were identified. Formalin-fixed, paraffin-embedded tissue blocks were retrieved, and p16 and DAP kinase promoter methylation status was determined by methylation specific PCR. Two-sided statistical analyses were performed to determine associations between methylation status, clinicopathologic characteristics, and survival. Results: DAP kinase and p16 methylation status was observed in 36.3% (97 of 267) and 36.4% (95 of 261) cases, respectively. Subject characteristics: 55% female, 77% former/current smokers, 81% stage I, 19% stage II, 61% adenocarcinoma, 29% squamous carcinoma, 63% performance status (PS) 0, 37% PS 1,93% < 5% weight loss. Recurrent NSCLC and death occurred in 21.3% and 38% of cases, respectively. No significant associations were observed between DAP kinase methylation status and subject characteristics. P16 methylation was associated with moderate/high grade (p = 0.03). A higher frequency of p16 methylation was observed in ever vs never smokers (39% vs 28%, p = 0.17). Preliminary analyses do not demonstrate significant associations between methylation status and overall survival (p16 p = 0.13; DAP kinase p = 0.56) or disease-free survival (p16 p = 0.36; DAP kinase p = 0.71). Conclusions: In this relatively large cohort of early-stage NSCLC patients, we did not detect significant associations between p16 and DAP kinase promoter methylation and clinical outcome. Further subset analyses stratified by gender and histology will be performed. The prognostic role of these biomarkers in NSCLC remains unclear. No significant financial relationships to disclose.