High Genomic Instability Predicts Survival in Metastatic High-Risk Neuroblastoma

• Published in: Neoplasia (New York, N.Y.) Vol. 14; no. 9; pp. 823 - IN10
• Main Authors: Stigliani, Sara, Coco, Simona, Moretti, Stefano, Oberthuer, Andrè, Fischer, Mattias, Theissen, Jessica, Gallox, Fabio, Garavent, Alberto, Berthold, Frank, Bonassi, Stefano, Tonini, Gian Paolo, Scaruffi, Paola
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2012; Elsevier
• Subjects: Child; Child, Preschool; Chromosome Aberrations; Comparative Genomic Hybridization; Computer Science; Gene Amplification; Gene Expression Profiling; Genomic Instability; Humans; Infant; N-Myc Proto-Oncogene Protein; Neoplasm Metastasis; Neoplasm Staging; Neuroblastoma - genetics; Neuroblastoma - mortality; Neuroblastoma - pathology; Nuclear Proteins - genetics; Oncogene Proteins - genetics; Oncology; Prognosis; event-free survival; Feature Extraction; neuroblastoma; HR; STGs; aCGH; MYCN-amplified; EFS; MCRs; MYCN single copy; overall survival; receiver operating characteristic; GE; Gene Ontology; CNAs; Gene Expression; OS; intrachromosome segmental aberrations; ROC; GO; high-risk; minimal common regions; significant targeted genes; ICSAs; copy number aberrations; MYCN; NB; array-based comparative genomic hybridization; FE; neuroblastema; forecast
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.121114

Abstract We aimed to identify novel molecular prognostic markers to better predict relapse risk estimate for children with high-risk (HR) metastatic neuroblastoma (NB). We performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR NBs. Children older than 1 year of age were categorized as “short survivors” (dead of disease within 5 years from diagnosis) and “long survivors” (alive with an overall survival time ≥ 5 years). We reported that patients with less than three segmental copy number aberrations in their tumor represent a molecularly defined subgroup with a high survival probability within the current HR group of patients. The complex genomic pattern is a prognostic marker independent of NB-associated chromosomal aberrations, i.e., MYCN amplification, 1p and 11q losses, and 17q gain. Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is mainly associated with loss of cell cycle control and deregulation of Rho guanosine triphosphates (GTPases) functioning in neuritogenesis. Tumors with MYCN amplification show a lower chromosome instability compared to MYCN single-copy NBs ( P = .0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives disruption of neuronal differentiation and reduction of cell adhesion process involved in tumor invasion and metastasis. Further validation studies are warranted to establish this as a risk stratification for patients.