title: MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data.
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.
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pasello
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Urso
authors.affiliation: Oncology Unit, Villa Scassi Hospital, Genova, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Mencoboni
authors.affiliation: Oncohematologic Department, Mesothelioma Unit, Oncology, SS Antonio e Biagio General Hospital, Alessandria, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Grosso
authors.affiliation: Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Ceresoli
authors.affiliation: Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lunardi
authors.affiliation: Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Stefania Edith
authors.initials: SE
authors.lastname: Vuljan
authors.affiliation: Department of Clinical and Experimental Oncology, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertorelle
authors.affiliation: Department of Clinical and Experimental Oncology, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Sacchetto
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.|Department of Clinical and Experimental Oncology, Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ciminale
authors.affiliation: Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Rea
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Favaretto
authors.affiliation: Department of Clinical and Experimental Oncology, Medical Oncology 2, Istituto Oncologico Veneto IRCCS Padova, Italy.|Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
authors.forename: PierFranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D008940:Mitotic Index; D015999:Multivariate Analysis; D009154:Mutation; D009336:Necrosis; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: HIF1alpha; MDM2; inflammation; mesothelioma; necrosis