title: Elevated transcript levels from the MDM2 P1 promoter and low p53 transcript levels are associated with poor prognosis in human pancreatic ductal adenocarcinoma.
abstract: OBJECTDIVES: Mouse double minute 2 is a key negative regulator of the p53 protein, a central node in the mediation of tumor suppression. The MDM2 gene contains 2 differently regulated promoters, MDM2-P1 and MDM2-P2, which differ strongly in their biological and clinical importance.
  
  
  METHODS
  We assess the clinical significance of the expression of messenger RNA (mRNA) transcripts originating from both MDM2 promoters, measured with quantitative reverse transcription polymerase chain reaction in microdissected tissues from 57 patients with pancreatic ductal adenocarcinoma (PDAC). Furthermore, we determine the clinical relevance of p53 mRNA transcript expression and incorporate the somatic p53 mutational status into our analyses.
  
  
  RESULTS
  Interestingly, elevated transcript levels from the P1 promoter, but not the P2 promoter, associate significantly with up to 6.3-fold increased relative risk for tumor-related death (Cox multivariate analysis: P = 0.013). Furthermore, transcripts originating from both MDM2 promoters are found to correlate significantly with p53 mRNA levels (up to r = 0.315; P = 0.017). In addition, low p53 mRNA expression associates with worse PDAC prognosis (relative risk = 2.28; P = 0.021).
  
  
  CONCLUSIONS
  This study presents the first differentiated analysis of the MDM2-P1, MDM2-P2, and p53 transcript expression in human PDAC and demonstrates the significant clinical implications of those transcripts. Furthermore, it suggests an additional facet in the regulation of MDM2 via its P1 promoter in this malignancy.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, The University of Ulm, Ulm, Germany. lukasz.grochola@ludwig.ox.ac.uk
authors.forename: Lukasz Filip
authors.initials: LF
authors.lastname: Grochola
authors.forename: Helge
authors.initials: H
authors.lastname: Taubert
authors.forename: Thomas
authors.initials: T
authors.lastname: Greither
authors.forename: Umesh
authors.initials: U
authors.lastname: Bhanot
authors.forename: Andrej
authors.initials: A
authors.lastname: Udelnow
authors.forename: Peter
authors.initials: P
authors.lastname: Würl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016009:Chi-Square Distribution; D015536:Down-Regulation; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D042282:Microdissection; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2