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. 2015 Mar 3;112(5):883-90.
doi: 10.1038/bjc.2015.27. Epub 2015 Feb 10.

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

R F H Walter  1 , F D Mairinger  2 , S Ting  2 , C Vollbrecht  3 , T Mairinger  4 , D Theegarten  3 , D C Christoph  5 , K W Schmid  2 , J Wohlschlaeger  2
Affiliations

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

R F H Walter et al. Br J Cancer. .

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.

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Figures

Figure 1
Figure 1
MDM2-immunoexpression-dependent overall survival of the patients from Essen.
Figure 2
Figure 2
(A) MDM2-dependent overall survival and (B) P14/ARF-dependent overall survival of the patients from Essen.
Figure 3
Figure 3
MDM2-immunoexpression-dependent progression-free survival of the patients from Essen.
Figure 4
Figure 4
(A) MDM2-dependent and (B) P14/ARF-dependent progression-free survival of the patients from Essen.
See this image and copyright information in PMC

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