p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb.
OBJECTIVE
To identify the prognostic relevance of the G1/S cell cycle regulator genes p16INK4a, p53, MDM2, and Rb in patients with resected ductal pancreatic cancer (PC).


BACKGROUND
The tumor suppressor genes p16INK4a, p53, and Rb are altered in PC in 27% to 95%, 40% to 70%, and 5%, respectively. The role of MDM2 is not clearly defined in PC. The prognostic value of these cell cycle regulators has not been clarified.


METHODS
Sixty-two patients with PC with complete follow-up who underwent potentially curative resections were included in the study. An extreme group analysis was performed including the 20 patients with the shortest survival and the 20 patients with the longest survival. Protein expression of p16, p53, MDM2, and Rb was investigated, and mutation analysis of p16INK4a and p53 was performed. p16INK4a promoter hypermethylation was examined by methylation-specific polymerase chain reaction.


RESULTS
Significantly more tumors in the shortest-surviving patients had p16INK4a alterations compared with tumors of the longest-surviving patients. In contrast, the frequency of p53 alterations was not significantly higher in the shortest-surviving versus the longest-surviving groups. Stabilization of MDM2 and loss of Rb expression were identified in a minority of tumors, independent of survival length.


CONCLUSIONS
The presence of p16INK4a alterations in resected tumors of patients with PC is connected with a worse prognosis, indicating patients that might benefit from adjuvant therapy regimens. p53 alterations, MDM2 overexpression, and loss of Rb expression could not be identified as prognostic markers from this study, but a larger study with greater statistical power might show a different result with regard to p53.
Gerdes
Berthold
B
Department of Visceral-, Thoracic-, and Vascular Surgery, Philipps University of Marburg, Marburg, Germany. gerdes@mailer.uni-marburg.de
Ramaswamy
Annette
A
Ziegler
Andreas
A
Lang
Sven A
SA
Kersting
Michael
M
Baumann
Renate
R
Wild
Anja
A
Moll
Roland
R
Rothmund
Matthias
M
Bartsch
Detlef K
DK
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm / Q000302:isolation & purification; D003627:Data Interpretation, Statistical; D016161:Genes, Retinoblastoma / Q000235:genetics; D019942:Genes, p16; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008745:Methylation; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins; D010183:Pancreatic Ducts; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2