Transcribed-ultra conserved region expression is associated with outcome in high-risk neuroblastoma

• Published in: BMC cancer Vol. 9; no. 1; p. 441
• Main Authors: Scaruffi, Paola, Stigliani, Sara, Moretti, Stefano, Coco, Simona, De Vecchi, Carla, Valdora, Francesca, Garaventa, Alberto, Bonassi, Stefano, Tonini, Gian Paolo
• Format: Journal Article
• Language: English
• Published: London BioMed Central 15.12.2009; BioMed Central Ltd; BMC
• Subjects: Base Sequence; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Care and treatment; Child, Preschool; Conserved Sequence; Development and progression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health Promotion and Disease Prevention; Humans; Medicine/Public Health; MicroRNAs - genetics; Neoplasm Staging; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - pathology; Neuroblastoma - therapy; Oncology; Patient outcomes; Physiological aspects; Pilot Projects; Research Article; Risk Factors; RNA; Surgical Oncology; Transcription, Genetic; Treatment Outcome; Italy; MYCN Gene; microRNA Expression Profile; Event Free Survival; Neuroblastoma; Overall Survival
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-9-441

Background Neuroblastoma is the most common, pediatric, extra-cranial, malignant solid tumor. Despite multimodal therapeutic protocols, outcome for children with a high-risk clinical phenotype remains poor, with long-term survival still less than 40%. Hereby, we evaluated the potential of non-coding RNA expression to predict outcome in high-risk, stage 4 neuroblastoma. Methods We analyzed expression of 481 Ultra Conserved Regions (UCRs) by reverse transcription-quantitative real-time PCR and of 723 microRNAs by microarrays in 34 high-risk, stage 4 neuroblastoma patients. Results First, the comparison of 8 short- versus 12 long-term survivors showed that 54 UCRs were significantly ( P < 0.0491) over-expressed in the former group. For 48 Ultra Conserved Region (UCRs) the expression levels above the cut-off values defined by ROC curves were strongly associated with good-outcome (OS: 0.0001 < P < 0.0185, EFS: 0.0001 < P < 0.0491). Then we tested the Transcribed-UCR (T-UCR) threshold risk-prediction model on an independent cohort of 14 patients. The expression profile of 28 T-UCRs was significantly associated to prognosis and at least 15 up-regulated T-UCRs are needed to discriminate ( P < 0.0001) short- from long-survivors at the highest sensitivity and specificity (94.12%). We also identified a signature of 13 microRNAs differently expressed between long- and short-surviving patients. The comparative analysis of the two classes of non-coding RNAs disclosed that 9 T-UCRs display their expression level that are inversely correlated with expression of 5 complementary microRNAs of the signature, indicating a negative regulation of T-UCRs by direct interaction with microRNAs. Moreover, 4 microRNAs down-regulated in tumors of long-survivors target 3 genes implicated in neuronal differentiation, that are known to be over-expressed in low-risk tumors. Conclusions Our pilot study suggests that a deregulation of the microRNA/T-UCR network may play an important role in the pathogenesis of neuroblastoma. After further validation on a larger independent set of samples, such findings may be applied as the first T-UCR prognostic signature for high-risk neuroblastoma patients.