Oncotarget

Research Papers:

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

Giulia Pasello, Loredana Urso, Manlio Mencoboni, Federica Grosso, Giovanni Luca Ceresoli, Francesca Lunardi, Stefania Edith Vuljan, Roberta Bertorelle, Valeria Sacchetto, Vincenzo Ciminale, Federico Rea, Adolfo Favaretto, PierFranco Conte and Fiorella Calabrese _

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Oncotarget. 2015; 6:42053-42066. https://doi.org/10.18632/oncotarget.5974

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Abstract

Giulia Pasello1,*, Loredana Urso2,*, Manlio Mencoboni3, Federica Grosso4, Giovanni Luca Ceresoli5, Francesca Lunardi6, Stefania Edith Vuljan6, Roberta Bertorelle7, Valeria Sacchetto7, Vincenzo Ciminale2,7, Federico Rea6, Adolfo Favaretto1, PierFranco Conte1,2, Fiorella Calabrese6

1Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy

2Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy

3Oncology Unit, Villa Scassi Hospital, Genova, Italy

4Oncohematologic Department, Mesothelioma Unit, Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy

5Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy

6Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy

7Department of Clinical and Experimental Oncology, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy

*These authors have contributed equally to this work

Correspondence to:

Fiorella Calabrese, e-mail: [email protected]

Keywords: mesothelioma, MDM2, HIF1alpha, inflammation, necrosis

Received: May 04, 2015     Accepted: October 20, 2015     Published: October 30, 2015

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.


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