title: Overall genomic pattern is a predictor of outcome in neuroblastoma.
abstract: OBJECTIVE
  For a comprehensive overview of the genetic alterations of neuroblastoma, their association and clinical significance, we conducted a whole-genome DNA copy number analysis.
  
  
  METHODS
  A series of 493 neuroblastoma (NB) samples was investigated by array-based comparative genomic hybridization in two consecutive steps (224, then 269 patients).
  
  
  RESULTS
  Genomic analysis identified several types of profiles. Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. Patients with both numerical and segmental abnormalities clearly shared the higher risk of relapse of segmental-only patients. In a multivariate analysis, taking into account the genomic profile, but also previously described individual genetic and clinical markers with prognostic significance, the presence of segmental alterations with (HR, 7.3; 95% CI, 3.7 to 14.5; P < .001) or without MYCN amplification (HR, 4.5; 95% CI, 2.4 to 8.4; P < .001) was the strongest predictor of relapse; the other significant variables were age older than 18 months (HR, 1.8; 95% CI, 1.2 to 2.8; P = .004) and stage 4 (HR, 1.8; 95% CI, 1.2 to 2.7; P = .005). Finally, within tumors showing segmental alterations, stage 4, age, MYCN amplification, 1p and 11q deletions, and 1q gain were independent predictors of decreased overall survival.
  
  
  CONCLUSIONS
  The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.
authors.affiliation: INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 26 rue d'Ulm, 75248 Paris Cedex 05, France. olivier.delattre@curie.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schleiermacher
authors.forename: Evi
authors.initials: E
authors.lastname: Michels
authors.forename: Véronique
authors.initials: V
authors.lastname: Mosseri
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Delphine
authors.initials: D
authors.lastname: Lequin
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Jérôme
authors.initials: J
authors.lastname: Couturier
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.forename: Dominique
authors.initials: D
authors.lastname: Plantaz
authors.forename: Hervé
authors.initials: H
authors.lastname: Rubie
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: Caroline
authors.initials: C
authors.lastname: Thomas
authors.forename: Valérie
authors.initials: V
authors.lastname: Combaret
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rousseau
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Jean
authors.initials: J
authors.lastname: Michon
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D014408:Biomarkers, Tumor; D055028:Comparative Genomic Hybridization; D004273:DNA, Neoplasm / Q000235:genetics*; D005500:Follow-Up Studies; D005784:Gene Amplification; D016259:Genes, myc; D042822:Genomic Instability; D006801:Humans; D007223:Infant; D015999:Multivariate Analysis; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm