Abstract
BackgroundThe prognosis of children with metastatic stage 4 neuroblastoma (NB) has remained poor in the past decade.Patients and methodsUsing microarray analyses of 342 primary tumors, we here developed and validated an easy to use gene expression-based risk score including 18 genes, which can robustly predict the outcome of stage 4 patients.ResultsThis classifier was a significant predictor of overall survival in two independent validation cohorts [cohort 1 (n = 214): P = 6.3 × 10−5; cohort 2 (n = 27): P = 3.1 × 10−2]. The prognostic value of the risk score was validated by multivariate analysis including the established markers age and MYCN status (P = 0.027). In the pooled validation cohorts (n = 241), integration of the risk score with the age and/or MYCN status identified subgroups with significantly differing overall survival (ranging from 35 to 100 %).ConclusionTogether, the 18-gene risk score classifier can identify patients with stage 4 NB with favorable outcome and may therefore improve risk assessment and treatment stratification of NB patients with disseminated disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0896-7) contains supplementary material, which is available to authorized users.
Highlights
The prognosis of children with metastatic stage 4 neuroblastoma (NB) has remained poor in the past decade
Our study has selected 520 unique probes for 426 genes as putative clinical markers based on the following sources: 1. 203 markers by Medline search through the PubMed database (1990–2014) by using the keywords “Neuronal marker” and “Neuroendocrine marker”. 115 articles were selected on the basis of the best available evidence for the specific question; 2. published gene-signatures (a) 112 genes Oberthuer et al [14] (b) 55 genes Asgharzadeh et al [12] (c) 59 genes Vermeulen et al [15] (d) 32 genes Fardin et al [16] (e) 14 genes Asgharzadeh et al [13]; 3. 101 genes/probes obtained by analysis of publicly available microarray of gene expression data (GSE9169) on different NB cell lines treated with retinoic acid (RA)
Selection of 18 genes for predicting overall survival in stage 4 NB The analytic approach based on a re-analysis of public data and the application of Cox regression and receiver operating characteristic (ROC) curve method (Fig. 1; Additional file 1: Fig. S1 and S2) allowed us to identify a signature as predictor of overall survival (OS) composed of 20 probes for 18 unique
Summary
The prognosis of children with metastatic stage 4 neuroblastoma (NB) has remained poor in the past decade. Neuroblastoma (NB) is the most frequent solid tumor of early childhood with a remarkable variation in clinical presentation ranging from favorable localized tumors that can spontaneously regress to metastatic disease with unfavorable outcome [1]. Another paper reviewed the clinical and survival data of 2216 children with NB enrolled in the Italian Neuroblastoma Registry over a 27-year period (1979–2005). From 1992 to 2005, the overall survival (OS) of patients with stage 3 significantly improved from 67.3 to 88.5 %, whereas the OS of stage 4 patients increased only by 3 % (26–29 %) [4]. These findings demonstrate that no substantial progress in survival has been made for stage 4 patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
