Abstract
BackgroundNeuroblastoma is the most common pediatric malignancy with heterogeneous clinical behaviors, ranging from spontaneous regression to aggressive progression. Many studies have identified aberrations related to the pathogenesis and prognosis, broadly classifying neuroblastoma patients into high- and low-risk groups, but predicting tumor progression and clinical management of high-risk patients remains a big challenge.ResultsWe integrate gene-level expression, array-based comparative genomic hybridization and functional gene-interaction network of 145 neuroblastoma patients to detect potential driver genes. The drivers are summarized into a driver-gene score (DGscore) for each patient, and we then validate its clinical relevance in terms of association with patient survival. Focusing on a subset of 48 clinically defined high-risk patients, we identify 193 recurrent regions of copy number alterations (CNAs), resulting in 274 altered genes whose copy-number gain or loss have parallel impact on the gene expression. Using a network enrichment analysis, we detect four common driver genes, ERCC6, HECTD2, KIAA1279, EMX2, and 66 patient-specific driver genes. Patients with high DGscore, thus carrying more copy-number-altered genes with correspondingly up- or down-regulated expression and functional implications, have worse survival than those with low DGscore (P = 0.006). Furthermore, Cox proportional-hazards regression analysis shows that, adjusted for age, tumor stage and MYCN amplification, DGscore is the only significant prognostic factor for high-risk neuroblastoma patients (P = 0.008).ConclusionsIntegration of genomic copy number alteration, expression and functional interaction-network data reveals clinically relevant and prognostic putative driver genes in high-risk neuroblastoma patients. The identified putative drivers are potential drug targets for individualized therapy.ReviewersThis article was reviewed by Armand Valsesia, Susmita Datta and Aleksandra Gruca.
Highlights
Neuroblastoma is the most common pediatric malignancy with heterogeneous clinical behaviors, ranging from spontaneous regression to aggressive progression
Driver genes in high-risk neuroblastoma Among 48 high-risk (HR) neuroblastoma patients, we identify 4058 copy-number alteration (CNA) with an average 84 and range 9~ 433
We annotate the CNAs based on probe-gene information available from original array-based comparative genomic hybridization (aCGH) data
Summary
Neuroblastoma is the most common pediatric malignancy with heterogeneous clinical behaviors, ranging from spontaneous regression to aggressive progression. Many studies have identified aberrations related to the pathogenesis and prognosis, broadly classifying neuroblastoma patients into high- and low-risk groups, but predicting tumor progression and clinical management of high-risk patients remains a big challenge. Neuroblastoma, an embryonal malignancy in sympathetic nervous system, is the most frequent extracranial solid tumor in very young children [1]. It accounts for 7% of pediatric oncology and 15% of childhood cancer deaths [2, 3]. The high-risk neuroblastoma can be identified at a chromosomal level by the presence of segmental aberrations, such as amplification, deletion and translocation. We hypothesize that additional clinically relevant structural alterations rather than point mutations might occur in high-risk neuroblastoma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
