P16 and MGMT hypermethylation predicts surgical outcomes in curative resected mid/distal bile duct cancer

Abstract

Extrahepatic bile duct cancer is a primary malignancy arising from epithelium of extrahepatic biliary tract. In patients with extrahepatic bile duct carcinoma, the 5-year survival rate was 38.3%; a very poor prognosis has been reported. In these patients, the important prognostic factors include the TNM stage, cell differentiation and histologic type. Nevertheless, we often encounter a substantial number of patients whose prognosis is not consistent with the TNM stage. Therefore, other prognostic criteria are mandatory than the TNM staging system which has been widely used at present. We aimed to evaluate the potential role of DNA promoter methylation of gene involved in a variety of celluar function including adhesion (CDH1), cell division (p16) and survival (DAPK), to predict disease free survival (DFS) and overall survival (OS) in curative resected mid/distal bile duct cancer. Sixty-five mid/distal bile duct carcinoma specimens obtained at Severance Hospital of Yonsei University College of Medicine from January 2000 to December 2006. Methylation of interest loci was confirmed using pyrosequecning.The significant methylation frequencies (MtI > 5%) of the 3 gene analyzed were 17% for P16, 54% for DAPK, 60% for E-cadherin. P16 and DAPK MtI status correlated with perineural invasion and tumor depth, respectively. In 65 patients, the 3-year and 5-year overall survival was 54.9% and 48.4%, respectively. In multivariate analysis of overall survival, presence of lymph node metastasis and P16 methylation status were identified as an independent prognostic factors for overall survival. In patient with unmethylated of P16, the 3- and 6-yeat survival rates were 60.8 % and 54.9 %, respectively. In patients with a hypermethylated of P16, the 3- and 6-yeat survival rates were 27.3 % and 0.0 %, respectively. P16 hypermethylation can 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 capability of predicting prognosis and of applying tailored therapy in mid/distal cancer.