Journal
ANNALS OF ONCOLOGY
Volume 25, Issue 10, Pages 2080-2086Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdu249
Keywords
Ewing sarcoma; miR-34a; cyclin D1; Ki-67; prognostic biomarkers
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Funding
- Italian Association for Cancer Research-AIRC [IG2013_14049]
- Italian Ministry of Health-TRANSCAN_Provabes
- fellowship 'Guglielmina Lucatello e Gino Mazzega' granted by Fondazione Italiana per la Ricerca sul Cancro-FIRC
- Associazione Onlus 'il Pensatore: Matteo Amitrano' and 'Liberi di Vivere Luca Righi'
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Background: At diagnosis, identification of reliable biological indicators of prognosis to allow stratification of patients according to different risks is an important but still unresolved aspect in the treatment of Ewing sarcoma (EWS) patients. This study aimed to explore the role of miR-34A expression on prognosis of EWS patients. Patients and methods: Specimens from 109 patients with non-metastatic EWS treated at the Rizzoli Institute with neoadjuvant chemotherapy (protocols ISG/SSGIII, EW-1, EW-2, EW-REN2, EW-REN3, EW-PILOT) and 17 metastases were studied. Sixty-eight patients (62%) remained disease-free and 41 (38%) relapsed (median follow-up: 67 months, range 9-241 months). Expression of miR-34a and of some of its targets (cyclin D1, bcl-2, SIRT1 and YY1) was evaluated by qRT-PCR using TaqMan MicroRNA Assays and/or by immunohistochemistry on tissue microarrays from the same patients. Results: High expression of miR-34a in localized tumors was significantly related to better event-free and overall survival (P = 0.004). Relevance of miR-34a was confirmed by using different calibrators (normal mesenchymal stem cells and different normal tissues). By multivariate Cox regression analysis, low miR-34a expression as well as nontotal necrosis and high levels of lactate dehydrogenase were all confirmed as independent risk factors associated with poor outcome. Expression of miR-34a was lower in metastases than in primary tumors. It inversely correlated with expression of cyclin D1 and Ki-67. Conclusions: By demonstrating its relationship with clinical outcome, we propose evaluation of miR-34a at diagnosis of EWS patients to allow early risk stratification. Validation of these results would nonetheless ultimately need a prospective assessment.
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