Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma.
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.
Scaruffi
Paola
P
Translational Paediatric Oncology, National Cancer Research Institute (IST), Genoa, Italy. paola.scaruffi@istge.it
Stigliani
Sara
S
Moretti
Stefano
S
Coco
Simona
S
De Vecchi
Carla
C
Valdora
Francesca
F
Garaventa
Alberto
A
Bonassi
Stefano
S
Tonini
Gian Paolo
GP
D001483:Base Sequence; D002675:Child, Preschool; D017124:Conserved Sequence; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D010865:Pilot Projects; D012307:Risk Factors; D014158:Transcription, Genetic; D016896:Treatment Outcome
D035683:MicroRNAs