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

Our plain-English summary of 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, by R.F. Walter, F.D. Mairinger, S. Ting, et al (British Journal of Cancer, 2015).

The study

• Authors: R.F. Walter, F.D. Mairinger, S. Ting, C. Vollbrecht, T. Mairinger, D. Theegarten, D.C. Christoph, K.W. Schmid, J. Wohlschlaeger
• Journal: British Journal of Cancer
• Published: 2015;112(5):883-90
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study examined stored tumour tissue from 72 patients with malignant pleural mesothelioma (MPM). The samples, dated 2004 to 2010, came from the database of the Institute of Pathology at University Hospital Essen, Germany. All patients had received cisplatin with pemetrexed. The authors measured the MDM2 protein in tumours from 65 patients, and the mRNA (gene activity) of MDM2 and P14/ARF in tumours from 48 patients. They compared these results with overall survival and with time until the disease progressed. Patients whose tumours had no MDM2 protein lived longer than those with MDM2 protein (hazard ratio 4.2 for MDM2-positive patients, 95% confidence interval 2.5 to 7.2). After 3 years, 29% of MDM2-negative patients were alive, against none of the MDM2-positive patients. Higher MDM2 mRNA was linked to shorter survival (hazard ratio 3.2, 1.5 to 6.9) and to faster progression. The P14/ARF results did not reach statistical significance. The authors concluded that MDM2 is a reliable prognostic and predictive marker in MPM. The study did not examine asbestos exposure. Some patient counts in the article do not add up.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective laboratory study of archived (formalin-fixed, paraffin-embedded) tumour specimens. MDM2 protein was measured by immunohistochemistry, and MDM2 and P14/ARF mRNA by quantitative PCR. Results were correlated with overall survival and progression-free survival.
• Who was studied: 72 patients with malignant pleural mesothelioma (61 male, 11 female; mean age 63.8 years) from the MPM database of the Institute of Pathology, University Hospital Essen, Germany, with samples from 2004 to 2010. By subtype, 59 were epithelioid, 6 biphasic and 4 sarcomatoid; subtype was unavailable for 3. 65 patients had evaluable MDM2 protein results, and 48 were analysed for mRNA.
• Exposure: The factors studied were tumour levels of MDM2 protein and mRNA and of P14/ARF mRNA, in patients who all received cisplatin with pemetrexed. Asbestos is mentioned only as background; the study did not assess the patients' asbestos exposure.
• Main results:
  • Median overall survival in the full group of 72 patients was 18.5 months.
  • MDM2 protein was found only in epithelioid MPM and in the epithelioid component of biphasic MPM.
  • In the 65 patients with protein results, lack of MDM2 protein was significantly associated with longer overall survival. On the linear scale the hazard ratio for MDM2-positive patients was 4.2 (95% CI 2.5 to 7.2), p less than 0.0001. On the logarithmic scale it was 10.7 (95% CI 4.5 to 25.6).
  • At 3 years, 29% of patients with MDM2-negative MPM were alive; none of the patients with MDM2-positive MPM were.
  • In the 48 patients with mRNA results, elevated MDM2 mRNA was significantly associated with shorter overall survival: hazard ratio 3.2 (95% CI 1.5 to 6.9), p = 0.0014, on the logarithmic scale.
  • Any MDM2 protein expression was associated with shorter progression-free survival. The hazard ratio for patients with MDM2 expression was 2.3 (95% CI 1.4 to 3.7) on the linear scale and 4.5 (95% CI 1.99 to 10.4) on the logarithmic scale.
  • Elevated MDM2 mRNA was associated with shorter progression-free survival: hazard ratio 2.6, p = 0.0072 on the logarithmic scale (95% CI 1.3 to 5.4).
  • P14/ARF mRNA showed no statistically significant correlation with overall survival (p = 0.38 linear, p = 0.13 logarithmic). Kaplan–Meier curves nonetheless separated patients with low expression from those with high expression.
  • For progression-free survival, P14/ARF mRNA showed only a statistical trend, with higher expression in patients with longer progression-free survival (p = 0.057 logarithmic, p = 0.62 linear).
  • In the group with protein results, male patients had shorter overall survival: hazard ratio 3.35 (95% CI 1.2 to 9.5).
• The authors' conclusion: The authors concluded that increased MDM2 expression correlated with decreased overall and progression-free survival, making MDM2 a reliable and robust prognostic and predictive biomarker in MPM. They also concluded that downregulation of P14/ARF seems to contribute to MDM2-mediated inactivation of P53.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, CDKN2A, Cisplatin, Biomarker, Overall Survival, Progression-Free Survival, Prognosis.

Related studies

• Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma — F.D. Mairinger, R.F. Walter, et al. (2014)
• The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours — S. Ammoun, M.C. Schmid, et al. (2015)
• An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression — T.T.T. Nguyen, M. Shingyoji, et al. (2021)
• microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma — R.F. Walter, C. Vollbrecht, et al. (2016)
• HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status — W.B. Ou, J. Zhu, et al. (2015)
• Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): value of 18F-FDG-PET/CT — N.G. Schaefer, P. Veit-Haibach, et al. (2012)

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