title: P16 hypermethylation predicts surgical outcome following curative resection of mid/distal bile duct cancer.
abstract: 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.
authors.affiliation: Pancreatobiliary Cancer Clinic, Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea.
authors.forename: Joon Seong
authors.initials: JS
authors.lastname: Park
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.forename: Kang Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Kim
authors.forename: Dong Sup
authors.initials: DS
authors.lastname: Yoon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D015820:Cadherins / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D019942:Genes, p16; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D011237:Predictive Value of Tests; D015996:Survival Rate; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D064550:Death-Associated Protein Kinases; D000070957:MutL Protein Homolog 1