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

Abstract

BackgroundNeuroblastoma 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.MethodsWe 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.ResultsFirst, 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.ConclusionsOur 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.

MicroRNA Target Signatures in Advanced Stage Neuroblastoma

“…Previous research has shown that miR-9 upregulation correlates with breast cancer metastasis (Ma et al, 2010), supporting our finding of miR-9 as a new biomarker for advanced neuroblastoma. Furthermore, we also found miR-9 to be significantly upregulated in short-term survival patients within the advanced stage neuroblastoma group in other publicly available data (Scaruffi et al, 2009), confirming the validity of our finding. To increase the specificity of differentiating high-risk and short-term survival groups, further research is needed to identify additional miR-9 activating factors besides MYCN as well as the common biological pathways of miR-9 target genes in neuroblasts (Fig.…”

“…Scaruffi et al published research on non-coding RNA expressions with regard to outcome in high-risk neuroblastoma (Scaruffi et al, 2009). Among 31 high-risk, stage 4 neuroblastoma samples, miRNA expressions came from 17 short-term survivors (dead within 36 months from diagnosis) and 14 long-term survivors (alive with an overall survival time > 36 months) were deposited in GEO (Series accession number GSE16444).…”

N-myc and Noncoding RNAs in Neuroblastoma

“…TUCRs are widely expressed in neuroblastoma, and a signature based on the expression of 28 T-UCRs has been shown to be associated with good outcome in noninfant patients with metastatic disease (84). Furthermore, Mestdagh and colleagues (85) investigated the global T-UCR expression in neuroblastoma and found a signature of 7 T-UCRs significantly upregulated in MYCN-amplified tumors (n ¼ 18) compared with nonamplified tumors (n ¼ 31).…”

Noncoding RNAs: Different roles in tumorigenesis

“…Scaruffi et al [48] suggested that deregulation of the microRNA/T-UCR network may play an important role in the pathogenesis of neuroblastoma and tumor-associated T-UCRs in CLL were found to be regulated by certain miRNAs [47]. These results led to the hypothesis that T-UCRs along with miRNAs may define signatures associated with the diagnosis, prognosis and treatment of tumors.…”