P16 Hypermethylation Predicts Surgical Outcome Following Curative Resection of Mid/Distal Bile Duct Cancer

BACKGROUND: Bile duct cancer has very poor prognosis. Important prognostic factors include the TNM stage, cell differentiation, and histologic type; however, we often observe patients whose prognosis is not consistent with the TNM stage. Additional prognostic indicators are mandatory to complement those used presently. We evaluated the hypermethylation status of genes for the power to predict overall survival following curative resection of mid/distal bile duct cancer. METHODS: Pyrosequencing hypermethylation status at the loci of interest was analyzed in 65 mid/distal bile duct carcinoma specimens obtained at Severance Hospital of Yonsei University College of Medicine from January 2000 to December 2006. RESULTS: Significant methylation frequencies (MtI >5 %) were obtained for 5 genes (which P16 [17 %], DAPK [54 %], E-cadherin [60 %], RASSF-1 [46.2 %], and hMLH1 [43.1 %]). MtI status of P16, DAPK, and RASSF-1 were correlated with perineural invasion, tumor depth, and age, respectively. In the multivariate analysis of overall survival, the presence of lymph node metastasis and P16 methylation status were identified as independent prognostic factors for overall survival. Patients with unmethylated of P16 had the 3- and 5-year survival rates of 60.8 and 54.9 %, respectively. In patients with hypermethylated P16, the 3- and 5-year survival rates were 27.3 and 0.0 %, respectively. CONCLUSIONS: P16 hypermethylation and lymph node metastasis may predict overall survival in curative resected mid/distal bile duct cancer. Classification of mid/distal bile duct cancer by both genetic and epigenetic profiles may improve the accuracy in predicting outcome and the effectiveness of tailored therapy in these diseases.ope