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

// Giulia Pasello 1, * , Loredana Urso 2, * , Manlio Mencoboni 3 , Federica Grosso 4 , Giovanni Luca Ceresoli 5 , Francesca Lunardi 6 , Stefania Edith Vuljan 6 , Roberta Bertorelle 7 , Valeria Sacchetto 7 , Vincenzo Ciminale 2, 7 , Federico Rea 6 , Adolfo Favaretto 1 , PierFranco Conte 1, 2 , Fiorella Calabrese 6 1 Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy 2 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy 3 Oncology Unit, Villa Scassi Hospital, Genova, Italy 4 Oncohematologic Department, Mesothelioma Unit, Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy 5 Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy 6 Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy 7 Department 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: fiorella.calabrese@unipd.it 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.