title: Expression of p16(INK4A) but not hypoxia markers or poly adenosine diphosphate-ribose polymerase is associated with improved survival in patients with pancreatic adenocarcinoma.
abstract: BACKGROUND
  Pancreatic cancer is associated with mutations in the tumor suppressor gene cyclin-dependent kinase inhibitor 2A (p16(INK4A) ), a regulator of the cell cycle and apoptosis. This study investigates whether immunohistochemical expression of p16(INK4A) as well as hypoxia markers and poly adenosine diphosphate-ribose polymerase (PARP) correlates with survival in patients with resected pancreatic adenocarcinoma.
  
  
  METHODS
  Seventy-three patients with pancreatic adenocarcinoma who underwent curative resection at Stanford University were included. From the surgical specimens, a tissue microarray was constructed using triplicate tissue cores from the primary tumor and used for immunohistochemical staining for the following markers: carbonic anhydrase IX, dihydrofolate reductase, p16(INK4A) , and PARP1/2. Staining was scored as either positive or negative and percentage positive staining. Staining score was correlated with overall survival (OS) and progression-free survival (PFS).
  
  
  RESULTS
  Of the markers tested, only immunohistochemical expression of p16(INK4A) correlated with clinical outcome. On univariate analysis, p16(INK4A) expression in the tumor was associated with improved OS (P = .038) but not PFS (P = .28). The median survival for patients with positive versus negative p16(INK4A) staining was 28.8 months versus 18 months. On multivariate analysis, p16(INK4A) expression was associated with improved OS (P = .026) but not PFS (P = .25). Age (P = .0019) and number of nodes involved (P = .025) were also significant for OS. Adjuvant chemotherapy and margin status did not correlate with OS or PFS.
  
  
  CONCLUSIONS
  Expression of p16(INK4A) is associated with improved OS in patients with resected pancreatic adenocarcinoma. Further investigation is needed for validation, given conflicting data in the published literature. .
authors.affiliation: Department of Radiation Oncology, Stanford University, Stanford, CA, USA. dtchang@stanford.edu
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chang
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Chapman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Norton
authors.forename: Brendan
authors.initials: B
authors.lastname: Visser
authors.forename: George A
authors.initials: GA
authors.lastname: Fisher
authors.forename: Pamela
authors.initials: P
authors.lastname: Kunz
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D015687:Cell Hypoxia; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D046888:Tissue Array Analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D013762:Tetrahydrofolate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases