title: MDM2 is an important prognostic and predictive factor for platin-pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed. Until now, predictive and prognostic biomarkers are lacking, making it a non-tailored therapy regimen with unknown outcome. P53 is frequently inactivated in MPM, but mutations are extremely rare. MDM2 and P14/ARF are upstream regulators of P53 that may contribute to P53 inactivation.
  
  
  METHODS
  A total of 72 MPM patients were investigated. MDM2 immunoexpression was assessed in 65 patients. MDM2 and P14/ARF mRNA expression was analysed in 48 patients of the overall collective. The expression results were correlated to overall survival (OS) and progression-free survival (PFS).
  
  
  RESULTS
  OS and PFS correlated highly significantly with MDM2 mRNA and protein expression, showing a dismal prognosis for patients with elevated MDM2 expression (for OS: Score (logrank) test: P⩽0.002, and for PFS: Score (logrank) test; P<0.007). MDM2 was identified as robust prognostic and predictive biomarker for MPM on the mRNA and protein level. P14/ARF mRNA expression reached no statistical significance, but Kaplan-Meier curves distinguished patients with low P14/ARF expression and hence shorter survival from patients with higher expression and prolonged survival.
  
  
  CONCLUSIONS
  MDM2 is a prognostic and predictive marker for a platin-pemetrexed therapy of patients with MPMs. Downregulation of P14/ARF expression seems to contribute to MDM2-overexpression-mediated P53 inactivation in MPM patients.
authors: 1] Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen, Tüschener Weg 40, Essen D-45239, Germany [2] Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: R F H
authors: RF
authors: Walter
authors: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: F D
authors: FD
authors: Mairinger
authors: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: S
authors: S
authors: Ting
authors: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors: C
authors: C
authors: Vollbrecht
authors: Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany.
authors: T
authors: T
authors: Mairinger
authors: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors: D
authors: D
authors: Theegarten
authors: 1] Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany [2] Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Aurora, CO, USA.
authors: D C
authors: DC
authors: Christoph
authors: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: K W
authors: KW
authors: Schmid
authors: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: J
authors: J
authors: Wohlschlaeger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005971:Glutamates; D009944:Organoplatinum Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000068437:Pemetrexed; D006147:Guanine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2