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

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

doi:10.18632/oncotarget.5974

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.

Highlights

Malignant pleural mesothelioma (MPM) is an aggressive tumor with increasing incidence in industrialized countries because of previous widespread exposure to asbestos and high refractoriness to chemotherapy and radiotherapy
Molecular pathogenesis of MPM is characterized by several gene mutations, including neurofibromatosis 2 (NF2), BRCA1-associated protein-1 (BAP-1) and deletion of the INK4A/ARF locus (70–80%) where the genes p14/ARF and p16/INK4A are located [9]. p14/ARF is crucial in controlling cell proliferation and inhibits Murine Double Minute 2 (MDM2) protein functions [10]
The poor prognosis of MPM patients, the ineffective treatment options, the absence of predictive markers for tailored treatment and the lack of knowledge about molecular pathways selectively activated in different histologic subtypes, constitute the rationale for translational studies in MPM

Summary

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive tumor with increasing incidence in industrialized countries because of previous widespread exposure to asbestos and high refractoriness to chemotherapy and radiotherapy. Recent studies tested biologic agents targeting key oncogenic pathways, including phosphatidylinositol3-kinase (PI3K)/mammalian target of Rapamycin (mTOR) pathways, histone deacetylases (HDAC), Nuclear Factor kB (NFkB) and neoangiogenesis [8]. None of these therapies proved to significantly impact the natural history of this neoplasm, reinforcing the need for new targets and drugs in MPM. P53 is mutated in about 50% of human cancers [13], while in tumors with wild-type p53 gene, the protein function may be lost because of MDM2 overexpression [14]. Wild-type p53 might be present in MPM specimen [17, 18], even though few data about MDM2 expression levels are available [19]

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