MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data

Our plain-English summary of MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data, by G. Pasello, L. Urso, M. Mencoboni, et al (Oncotarget, 2015).

The study

• Authors: G. Pasello, L. Urso, M. Mencoboni, F. Grosso, G.L. Ceresoli, F. Lunardi, S.E. Vuljan, R. Bertorelle, V. Sacchetto, V. Ciminale, F. Rea, A. Favaretto, P. Conte, F. Calabrese
• Journal: Oncotarget
• Published: 2015;6(39):42053-66
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited treatment options. Sarcomatoid/biphasic mesotheliomas are characterized by more aggressive behaviour and a poorer prognosis compared with the epithelioid subtype. To date prognostic and tailored therapeutic biomarkers are lacking. The present study analyzed the expression levels of MDM2 and HIF1alpha in different histologic subtypes from chemonaive MPM patients. Diagnostic biopsies of MPM patients from four Italian cancer centers were centrally collected and analyzed. MDM2 and HIF1alpha expression levels were investigated through immunohistochemistry and RT-qPCR. Pathological assessment of necrosis, inflammation and proliferation index was also performed. Molecular markers, pathological features and clinical characteristics were correlated to overall survival (OS) and progression free survival (PFS). Sixty MPM patients were included in the study (32 epithelioid and 28 non-epithelioid). Higher levels of MDM2 (p < 0.001), HIF1alpha (p = 0.013), necrosis (p = 0.013) and proliferation index (p < 0.001) were seen mainly in sarcomatoid/biphasic subtypes. Higher levels of inflammation were significantly associated with epithelioid subtype (p = 0.044). MDM2 expression levels were correlated with HIF1alpha levels (p = 0.0001), necrosis (p = 0.008) and proliferation index (p = 0.009). Univariate analysis showed a significant correlation of non-epithelioid histology (p = 0.04), high levels of necrosis (p = 0.037) and proliferation index (p = 0.0002) with shorter PFS. Sarcomatoid/biphasic and epithelioid mesotheliomas showed different MDM2 and HIF1alpha expression levels and were characterized by different levels of necrosis, proliferation and inflammation. Further studies are warranted to confirm a prognostic and predictive role of such markers and features.

In plain English

This study examined tumour biopsies from 60 patients with malignant pleural mesothelioma (cancer of the lining around the lungs) who had not yet had chemotherapy. The samples came from four Italian cancer centers, with patients included from April 2007 to November 2014. The study did not measure asbestos exposure. The authors compared 32 epithelioid tumours with 28 non-epithelioid tumours (13 biphasic and 15 sarcomatoid). They measured two proteins, MDM2 and HIF1alpha. They also measured dead tissue (necrosis), inflammation, and the percentage of cells stained for the cell-division marker Ki67 (proliferation index). MDM2, HIF1alpha, necrosis and proliferation were higher in the sarcomatoid/biphasic group. Inflammation was higher in the epithelioid group. Epithelioid patients went longer before disease progression or death (median 41 versus 21 weeks). Their longer overall survival (67 versus 35 weeks) was not statistically significant. Median survival times differed by MDM2 level, but not statistically significantly. When other factors were taken into account, tumour type, necrosis and proliferation were no longer significant. The authors concluded that the two main subtypes differ biologically. They noted a small sample size and short follow-up for some patients.

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: Laboratory and pathology study of stored diagnostic biopsy samples, with clinical information collected retrospectively and compared with survival
• Who was studied: 60 chemotherapy-naive malignant pleural mesothelioma patients from four Italian cancer centers, included April 2007 to November 2014: 32 epithelioid (Group 1) and 28 non-epithelioid (13 biphasic, 15 sarcomatoid; Group 2). Median age 70; 51 males and 9 females
• Exposure: Asbestos exposure was not assessed. By histologic subtype, the study measured the tumour markers MDM2 and HIF1alpha (by immunohistochemistry and RT-qPCR), plus necrosis, inflammation and proliferation index. Proliferation index was the percentage of Ki67-positive cells
• Main results:
  • By immunohistochemistry, MDM2 and HIF1alpha levels were higher in the sarcomatoid/biphasic group than in the epithelioid group (p < 0.001 and p = 0.013). Median percentages of positive cells were 30 versus 10 for MDM2 and 40 versus 7.5 for HIF1alpha
  • MDM2 mRNA levels were higher in the sarcomatoid/biphasic group (p = 0.009; 46 patients evaluable by RT-qPCR). HIF1alpha mRNA was not associated with subtype (p = 0.17)
  • Across tumour samples, MDM2 and HIF1alpha protein levels were positively correlated (correlation coefficient 0.5; p = 0.0001)
  • Inflammation was higher in the epithelioid group (p = 0.044). Necrosis (p = 0.013) and proliferation index (p < 0.001) were higher in the sarcomatoid/biphasic group
  • Considering all patients, MDM2 levels correlated with necrosis (coefficient 0.34; p 0.008) and with Ki67 (coefficient 0.34; p 0.009)
  • No p53 mutations were found in the 10 samples tested, which were split equally between the two groups
  • Progression-free survival (time to disease progression or death) was longer in the epithelioid group (median 41 versus 21 weeks; p 0.04). Overall survival was longer but not statistically significant (median 67 versus 35 weeks; p = 0.1). Nine patients were lost to follow-up
  • Patients with low and high MDM2 levels had median overall survival of 60 versus 40 weeks (p = 0.3) and median progression-free survival of 40 versus 27 weeks (p = 0.2). Neither difference was statistically significant
  • High necrosis was linked to shorter progression-free survival (p = 0.037). High proliferation index was linked to shorter overall survival (p = 0.03) and shorter progression-free survival (p = 0.0002)
  • In multivariate analysis, the links of histology, necrosis and Ki67 with progression-free survival were not confirmed. EORTC prognostic score, surgery and subsequent treatment lines were significant for overall survival
• The authors' conclusion: The authors concluded that sarcomatoid/biphasic and epithelioid mesotheliomas differ in MDM2 and HIF1alpha levels and in necrosis, proliferation and inflammation. They stated that further studies are needed to confirm any prognostic or predictive role of these markers
• Limitations the authors state:
  • The authors stated that the small sample size may explain the lack of significant survival correlations. This applied especially to sarcomatoid/biphasic patients, few of whom had survival data
  • The authors stated that the most recently included patients had insufficient follow-up time
  • The authors stated that biphasic cases were few (13 of 60) and were grouped with sarcomatoid cases to increase statistical power

Topics

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

Medical terms in this study, explained in our Lexicon: Histological Subtype, Pleural Mesothelioma, Prognosis, Sarcomatoid, Biphasic Mesothelioma, Epithelioid, Biomarker, Immunohistochemistry.

Related studies

• Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma — F.D. Mairinger, R.F. Walter, et al. (2014)
• Two Different Serum MiRNA Signatures Correlate with the Clinical Outcome and Histological Subtype in Pleural Malignant Mesothelioma Patients — M. Lamberti, R. Capasso, 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)
• Critical review about MDM2 in cancer: Possible role in malignant mesothelioma and implications for treatment — L. Urso, F. Calabrese, et al. (2016)
• Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists — L. Urso, I. Cavallari, et al. (2017)
• 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. Walter, F.D. Mairinger, et al. (2015)

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