• Sergio Marchini, Duccio Cavalieri, Robert Fruscio, Enrica Calura, Daniela Garavaglia, Ilaria Fuso Nerini, Costantino Mangioni, Giorgio Cattoretti, Luca Clivio, Luca Beltrame, Dionyssios Katsaros, Luca Scarampi, Guido Menato, Patrizia Perego, Giovanna Chiorino, Alessandro Buda, Chiara Romualdi, and Maurizio D'Incalci.
• Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
• Lancet Oncol. 2011 Mar 1; 12 (3): 273-85.

BackgroundInternational Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer (EOC) has a significantly better prognosis than stage III/IV EOC, with about 80% of patients surviving at 5 years (compared with about 20% of those with stage III/IV EOC). However, 20% of patients with stage I EOC relapse within 5 years. It is therefore crucial that the biological properties of stage I EOCs are further elucidated. MicroRNAs (miRNAs) have shown diagnostic and prognostic potential in stage III and IV EOCs, but the small number of patients diagnosed with stage I EOC has so far prevented an investigation of its molecular features. We profiled miRNA expression in stage I EOC tumours to assess whether there is a miRNA signature associated with overall and progression-free survival (PFS) in stage I EOC.MethodsWe analysed tumour samples from 144 patients (29 of whom relapsed) with stage I EOC gathered from two independent tumour tissue collections (A and B), both with a median follow-up of 9 years. 89 samples from tumour tissue collection A were stratified into a training set (51 samples, 15 of which were from patients who relapsed) for miRNA signature generation, and into a validation set (38 samples, seven of which were from patients who relapsed) for signature validation. Tumour tissue collection B (55 samples, seven of which were from patients who relapsed) was used as an independent test set. The Cox proportional hazards model and the log-rank test were used to assess the correlation of quantitative reverse transcription PCR (qRT-PCR)-validated miRNAs with overall survival and PFS.FindingsA signature of 34 miRNAs associated with survival was generated by microarray analysis in the training set. In both the training set and validation set, qRT-PCR analysis confirmed that 11 miRNAs (miR-214, miR-199a-3p, miR-199a-5p, miR-145, miR-200b, miR-30a, miR-30a*, miR-30d, miR-200c, miR-20a, and miR-143) were expressed differently in relapsers compared with non-relapsers. Three of these miRNAs (miR-200c, miR-199a-3p, miR-199a-5p) were associated with PFS, overall survival, or both in multivariate analysis. qRT-PCR analysis in the test set confirmed the downregulation of miR-200c in relapsers compared with non-relapsers, but not the upregulation of miR-199a-3p and miR-199a-5p. Multivariate analysis confirmed that downregulation of miR-200c in the test set was associated with overall survival (HR 0·094, 95% CI 0·012-0·766, p=0·0272) and PFS (0·035, 0·004-0·311; p=0·0026), independent of clinical covariates.InterpretationmiR-200c has potential as a predictor of survival, and is a biomarker of relapse, in stage I EOC.FundingNerina and Mario Mattioli Foundation, Cariplo Foundation (Grant Number 2010-0744), and the Italian Association for Cancer Research.Copyright © 2011 Elsevier Ltd. All rights reserved.

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