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Background: Neuroblastoma (NB) is the most common solid tumour in childhood, and rises in the sympathetic nervous system. Here, we addressed the in silico analysis of the association between the expression of H2AFX gene involved in DNA damage response, and the survival of a cohort of 786 NB patients., Methods: In silico gene expression was retrieved from the publicly available dataset summarised by Cangelosi et al., including 13,696 gene expression profiles of 786 NB tumours at onset of disease. The prognostic value of H2AFX (H2A histone family member X) gene expression for event-free survival (EFS) and overall survival (OS) was evaluated by Kaplan-Meier and Cox regression analysis. The main results were validated on another openly accessible in silico database (NRC-283) containing 13,489 gene expressions in 283 NB patients. The expression of H2AFX protein was then tested by immunofluorescence on 48 primary NB samples of different tumour stages. H2AFX activity as an oncogene has been further validated in vitro by silencing the molecule in two NB cell lines, characterised by MYCN amplified or not, and performing cell growth and migration assays., Results: A strong inverse association between H2AFX expression and patients' survival was observed and confirmed by immunofluorescence results on primary NB tissue sections. Cox regression analysis also disclosed H2AFX as an independent predictor of EFS and OS. The gene-silencing experiments strongly suggested an oncogenic role for H2AFX on NB cells, regardless of MYCN amplification., Conclusions: H2AFX is a prognostic marker for unfavourable NB and could be considered a target for therapeutic interventions., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication., Procedure: Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios., Results: The cohort included 1053 patients with median follow-up 5.5 years and EFS 27 ± 1%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi-variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250 U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 ± 9% for score = 0 versus 6 ± 3% for score = 5 (P < 0.0001)., Conclusions: A simple score can identify an "ultra-high risk" (UHR) cohort (score = 5) comprising 8% of patients with 5-year EFS <10%. These patients appear not to benefit from induction therapy and could potentially be directed earlier to alternative experimental therapies in future trials., (© 2018 Wiley Periodicals, Inc.)

As a sympathetic nervous system-derived tumor, aggressive neuroblastoma (NB) is currently attracting interest from researchers seeking diagnostic and prognostic markers via less invasive procedures. The analysis of circulating tumor DNA (ctDNA) in peripheral blood can provide genetic information from multiple tumor lesions and is not dependent on a surgical procedure. The identification of genetic alterations, chromosomal variations, and hypermethylation contained within plasma DNA yields clinical value in the diagnosis, risk stratification, monitoring of treatment effects, and survival prediction for patients. With the widespread application of genome sequencing, droplet digital polymerase chain reaction, and other advanced technologies, the detection of ctDNA may guide therapeutic schedules, enhance the quality of life, and improve the prognosis for patients with NB., (© 2020 Wiley Periodicals, Inc.)

Background: Retrospective studies have demonstrated the prognostic impact of genomic profiles in neuroblastoma (NB). Segmental chromosome alterations have been found useful for identifying tumors with a high risk of relapse. As the gain of chromosome arm 17q is the most frequent chromosome alteration reported in NB primary tumors, we evaluated the presence of this 17q gain in the peripheral blood of patients with NB., Procedure: Using duplex quantitative real-time PCR, we quantified simultaneously MPO (17q.23.1) and a reference gene, p53, and Survivin (17q25) and p53. MPO and Survivin copy numbers were evaluated as MPO/p53 and Survivin/p53 ratios in 142 serum or plasma samples in which 17q status had been determined by array-based comparative genomic hybridization (aCGH) or multiplex ligation-dependent probe amplification (MLPA)., Results: In patients <18 months of age, serum-based determination of 17q gain in DNA sequences had good specificity (94.4%) and 58.8% sensitivity (P < 0.001). In contrast, for patients over 18 months of age, the approach exhibited moderate specificity (71.4%) and 51.2% sensitivity (P = ns). Similar results were observed in patients with tumors without MYCN amplification., Conclusion: Our results show that 17q gain determination in circulating DNA is possible and suggest that this non-invasive test could be useful for very young children when no reliable information on genomic alterations is obtained by aCGH or MPLA analysis of tumor samples This test is complementary to previously developed techniques for detecting circulating MYCN DNA sequences., (Copyright © 2011 Wiley-Liss, Inc.)