Chiara Romualdi
Published: 2017
Total Pages:
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Integrated pathway analysis identifies a 3-gene signature predicting platinum response and outcome of high-grade serous ovarian carcinoma patientsEliana Bignotti1,2u00a7, Giuseppe Benvenuto3u00a7, Lara Paracchini4u00a7, Laura Zanotti1, Chiara Romani1,5, Germana Tognon2, Enrica Calura3, Debora Vicini6, Marco Adorni6, Maria Chiara Paderno6, Tommaso Bianchi6, Franco E. Odicino7, Enrico Sartori7, Antonella Ravaggi1, Maurizio Du2019Incalci4, Paola Todeschini1*, Sergio Marchini4*, Chiara Romualdi 3* 1'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST-Spedali Civili of Brescia, Brescia, Italy; 2Division of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy; 3Department of Biology, University of Padova, Padova, Italy; 4Department of Oncology, IRCCS - u201cMario Negriu201d Institute for Pharmacological Research, Milano, Italy; 5Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; 6Clinic of Obstetrics and Gynecology, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy; 7Department of Clinical and Experimental Sciences, Division of Obstetrics and Gynecology University of Brescia, Brescia, Italy.u00a7EB, GB and LP contribute equally to this work*PT, SM and CR are co-last authorsIntroduction/BackgroundHigh-grade serous ovarian carcinoma (HGSOC), the most common and deadly epithelial ovarian cancer histotype is characterized by a heterogeneous genomic landscape. After surgery, all patients are treated with adjuvant platinum (Pt)-based chemotherapy to which the response is heterogeneous, ranging from cases sensitive (Platinum-sensitive, Pt-s cases), to intrinsically resistant patients, who relapse within 6 months from the end of therapy (Pt-resistant, Pt-r). The aim of the study was to investigate the mechanisms characterizing the biology of primary resistance to upfront Pt-based chemotherapy through an integrated pathway analysis.MethodologyGene and miRNA microarray experiments were carried out on 36 Pt-s and 41 Pt-r tumor samples. Gene and miRNA expression have been integrated using Micrographite algorithm. Expression levels of selected predictive and prognostic genes were validated on a total of 242 HGSOC samples by qRT-PCR and on the Curated Ovarian Database (including 838 HGSOC).ResultsExpression profiles of 131 mRNAs and five miRNAs, belonging to five different and functionally-related molecular pathways, discriminate Pt-s and Pt-r cases. We selected 23 elements of the networks for orthogonal validation and 19 coding genes confirmed as differentially expressed between Pt-r and Pt-s cases. Among them, 16 elements also showed independent prognostic value in terms of PFS and OS in multivariate analysis. The prognostic impact of this signature was in silico validated on the Curated Ovarian Database, resulting in a 3-gene signature as independent prognostic biomarker of survival for HGSOC.ConclusionIn the current study, we used an integrated pathway analysis on miRNA and gene expression signatures to capture the key pathways shaping the different biology of Pt-r and Pt-s tumors, validating our results using two independent cohorts of HGSOC biopsies. Finally, we investigated the association of the validated signature with survival across multiple HGSOC databases. This strategy identified a three-gene signature with predictive and prognostic impact in HGSOC.