title: Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer.
abstract: OBJECTIVE
  The goal of this retrospective study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4).
  
  
  BACKGROUND
  Recent whole-exome sequencing had shown that the landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for 4 frequently mutated genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4).
  
  
  METHODS
  We determined immunohistochemically the status of TP53, CDKN2A/p16, and SMAD4/DPC4 among the 4 genes because the KRAS gene is mutated in virtually all PDAC patients, and analyzed relationships with clinicopathological findings, including survival and patterns of disease progression, in 106 patients with PDAC undergoing radical surgery.
  
  
  RESULTS
  Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16 and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P < 0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P < 0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing number of alterations reflected poorer survival.
  
  
  CONCLUSIONS
  Genetic alterations of these 3 genes and their accumulation are strongly associated with malignant behavior of PDAC. Their immunohistochemical assessment at the time of diagnosis may provide a new prognostic tool, assisting in deciding optimal therapeutic strategies for patients.
authors.affiliation: Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Oshima
authors.forename: Keiichi
authors.initials: K
authors.lastname: Okano
authors.forename: Shinobu
authors.initials: S
authors.lastname: Muraki
authors.forename: Reiji
authors.initials: R
authors.lastname: Haba
authors.forename: Takashi
authors.initials: T
authors.lastname: Maeba
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000601:surgery*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D016158:Genes, p53; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000601:surgery*; D016577:Pancreaticoduodenectomy; D012189:Retrospective Studies; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005819:Genetic Markers; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53