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Mechanisms of neuroblastoma regression.

ABSTRACT: Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches.

SUBMITTER: Brodeur GM

PROVIDER: S-EPMC4244231 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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Mechanisms of neuroblastoma regression.

Brodeur Garrett M GM Bagatell Rochelle R

Nature reviews. Clinical oncology 20141021 12

Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, l ...[more]

PMID: 25331179

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Project description:BackgroundTelomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved.MethodsWhole genome sequencing (WGS) data of 68 primary neuroblastoma samples were analyzed. Telomere length was calculated from WGS data or by telomere restriction fragment analysis (n = 39). ALT was assessed by C-circle assay (CCA, n = 67) and detection of ALT-associated PML nuclear bodies (APB) by combined fluorescence in situ hybridization and immunofluorescence staining (n = 68). RNA sequencing was performed (n = 64) to determine expression of TERT and telomeric long non-coding RNA (TERRA). Telomerase activity was examined by telomerase repeat amplification protocol (TRAP, n = 15).ResultsTumors were considered as telomerase-positive if they harbored a TERT rearrangement, MYCN amplification or high TERT expression (45.6%, 31/68), and ALT-positive if they were positive for APB and CCA (19.1%, 13/68). If all these markers were absent, tumors were considered TMM-negative (25.0%, 17/68). According to these criteria, the majority of samples were classified unambiguously (89.7%, 61/68). Assessment of additional ALT-associated parameters clarified the TMM status of the remaining seven cases with high likelihood: ALT-positive tumors had higher TERRA expression, longer telomeres, more telomere insertions, a characteristic pattern of telomere variant repeats, and were associated with ATRX mutations.ConclusionsWe here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

Project description:BackgroundThe association between long noncoding RNAs (lncRNAs) and spontaneous regression of neuroblastoma (NB) has rarely been investigated and remains unknown.ObjectiveTo identify prognostic lncRNAs involved in the spontaneous regression of NB.MethodsDifferential expression analyses were performed between those samples with an outcome of death in stage 4 NB group and those samples with an outcome of survival in stage 4S NB group in two independent public datasets, respectively. Univariate Cox proportional hazard regression survival analysis was performed in each of the entire cohort to identify those lncRNAs significantly associated with overall survival (OS). Those lncRNAs independently associated with OS were then identified by multivariate Cox survival analysis and used to construct an lncRNA risk score.ResultsA total of 20 differentially expressed and survival-related lncRNAs were identified sharing between the two independent cohorts. The expression of each of these 20 lncRNAs was significantly correlated with the expression of NTRK1, which is a well-known factor involved in NB spontaneous regression. Four lncRNAs (LNC00839, FIRRE, LOC283177, and LOC101928100) were identified to be significantly associated with survival independent with each other and a four-lncRNA signature risk score was constructed. Patients with high lncRNA signature risk score had a significantly poorer OS and event-free survival than those with low lncRNA signature risk score. The four-lncRNA signature has a good performance in predicting survival independent with MYCN amplification (nonamplified vs amplified), age status (<18 months vs ≥18 months), risk status (low risk vs high risk), and International Neuroblastoma Staging System (INSS) stage (INSS 1/2/3/4S vs INSS 4).ConclusionsWe identified 20 survival-related lncRNAs that might be associated with the spontaneous regression of NB and developed a four-lncRNA signature risk score. The four-lncRNA signature is an independent prognostic factor for survival of NB patients.

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.

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Mechanisms of neuroblastoma regression.

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Mechanisms of neuroblastoma regression.

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