title: High genomic instability predicts survival in metastatic high-risk neuroblastoma.
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.
authors.affiliation: Center of Physiopathology of Human Reproduction, Department of Obstetrics and Gynecology, IRCCS San Martino Hospital, National Cancer Research Institute (IST), Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Stigliani
authors.forename: Simona
authors.initials: S
authors.lastname: Coco
authors.forename: Stefano
authors.initials: S
authors.lastname: Moretti
authors.forename: Andrè
authors.initials: A
authors.lastname: Oberthuer
authors.forename: Mattias
authors.initials: M
authors.lastname: Fischer
authors.forename: Jessica
authors.initials: J
authors.lastname: Theissen
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallo
authors.forename: Alberto
authors.initials: A
authors.lastname: Garavent
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonassi
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Paola
authors.initials: P
authors.lastname: Scaruffi
mesh_terms: D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D005784:Gene Amplification; D020869:Gene Expression Profiling; D042822:Genomic Instability; D006801:Humans; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D011379:Prognosis
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins