Identification of a chrXq27.3 microRNA cluster associated with early relapse in advanced stage ovarian cancer patients

Marina Bagnoli 1,§ , Loris De Cecco 1,§ , Anna Granata 1 , Roberta Nicoletti 1 , Edoardo Marchesi 1 , Paola Alberti 1 , Barbara Valeri 2 , Massimo Libra 3 , Mattia Barbareschi 4 , Francesco Raspagliesi 5 , Delia Mezzanzanica 1,# , Silvana Canevari 1,# 1 Depts. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Department of Pathology and Oncologic Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Department of General Pathology, University of Catania, Italy 4 Department of Pathology, Ospedale Santa Chiara, Trento, Italy 5 Department of Oncologic Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy § equally contributing first authors # equally contributing last authors Received: December 23, 2011; Accepted: December 30, 2011; Published: December 31, 2011; Keywords: advanced-stage ovarian cancer, early relapse, microRNA profiling, miR-506, cisplatin, miR-513a-5p, miR-513b Correspondence: Silvana Canevari, email: // // Abstract A major challenge in advanced-stage epithelial ovarian cancer (EOC) is prediction of chemoresistant relapse. Our aim was to identify a microRNA (miRNA) signature associated with early relapse in advanced-stage EOC patients. miRNA expression was assessed by microarray profiling in training ( n = 55 ) and test ( n = 30 ) sets selected on the basis of time to relapse (TTR), followed by internal quantitative reverse transcriptase-PCR validation on a set of 45 consecutive cases unselected for clinical response and external in silico validation on publicly available datasets. Thirty-two differentially expressed miRNAs in early vs. late relapsing patients were identified in the training set. In the test set, 8 of these, belonging to a cluster located on chrXq27.3, were down-modulated in early relapsing patients. Hierarchical clustering of the internal validation set according to chrXq27.3 miRNA expression associated low miRNA expression with shorter TTR (log-rank P=0.00074 , HR 2.44). The cluster was an independent prognostic factor in both internal and external validation sets. Forced expression of chrXq27.3-cluster selected miRNAs in human EOC cellular models was associated to reduction of cell proliferation and increased sensitivity to cisplatin. The role of down-modulation of the chrXq27.3 miRNA cluster in early relapse of advanced-stage EOC patients and its association to a reduced sensitivity to chemotherapeutic treatments warrant further investigation.