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Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma.

ABSTRACT: 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

SUBMITTER: Scaruffi P

PROVIDER: S-EPMC2804711 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma.

Scaruffi Paola P 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

BMC cancer 20091215

<h4>Background</h4>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.<h4>Methods</h4>We analyzed expression of 481 Ultra Conserved Regions (UCRs) by reverse transcription-quantitative real-t ...[more]

PMID: 20003513

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Project description:Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay [a marker for alternative lengthening of telomeres (ALT)], TERT mRNA expression by RNA-sequencing, whole-genome/exome sequencing, and clinical covariates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines (n = 104) and patient-derived xenografts (n = 28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in ATRX were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. Patients with high-risk neuroblastoma were classified into three subgroups (TERT-high, ALT+, and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT+, or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; P < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior OS (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets. SIGNIFICANCE: These findings assess telomere maintenance mechanisms with TERT mRNA and the ALT DNA biomarker C-circles to stratify neuroblastoma into three groups, with distinct overall survival independent of currently used clinical risk classifiers.

Project description:BackgroundCurrent clinical risk factors stratify patients with neuroblastoma (NB) for appropriate treatments, yet patients with similar clinical behaviors evoke variable responses. MYCN amplification is one of the established drivers of NB and, when combined with high-risk displays, worsens outcomes. Growing high-throughput transcriptomics studies suggest long noncoding RNA (lncRNA) dysregulation in cancers, including NB. However, expression-based lncRNA signatures are altered by MYCN amplification, which is associated with high-risk, and patient prognosis remains limited.MethodsWe investigated RNA-seq-based expression profiles of lncRNAs in MYCN status and risk status in a discovery cohort (n = 493) and validated them in three independent cohorts. In the discovery cohort, a prognostic association of lncRNAs was determined by univariate Cox regression and integrated into a signature using the risk score method. A novel risk score threshold selection criterion was developed to stratify patients into risk groups. Outcomes by risk group and clinical subgroup were assessed using Kaplan-Meier survival curves and multivariable Cox regression. The performance of lncRNA signatures was evaluated by receiver operating characteristic curve. All statistical tests were two-sided.ResultsIn the discovery cohort, 16 lncRNAs that were differentially expressed (fold change ≥ 2 and adjusted P ≤ 0.01) integrated into a prognostic signature. A high risk score group of lncRNA signature had poor event-free survival (EFS; P < 1E-16). Notably, lncRNA signature was independent of other clinical risk factors when predicting EFS (hazard ratio = 3.21, P = 5.95E-07). The findings were confirmed in independent cohorts (P = 2.86E-02, P = 6.18E-03, P = 9.39E-03, respectively). Finally, the lncRNA signature had higher accuracy for EFS prediction (area under the curve = 0.788, 95% confidence interval = 0.746 to 0.831).ConclusionsHere, we report the first (to our knowledge) RNA-seq 16-lncRNA prognostic signature for NB that may contribute to precise clinical stratification and EFS prediction.

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Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma.

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Transcribed-Ultra Conserved Region expression is associated with outcome in high-risk neuroblastoma.

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