Overall genomic pattern is a predictor of outcome in neuroblastoma.
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.
Janoueix-Lerosey
Isabelle
I
INSERM U830, Laboratoire de Génétique et Biologie des Cancers, 26 rue d'Ulm, 75248 Paris Cedex 05, France. olivier.delattre@curie.fr
Schleiermacher
Gudrun
G
Michels
Evi
E
Mosseri
Véronique
V
Ribeiro
Agnès
A
Lequin
Delphine
D
Vermeulen
Joëlle
J
Couturier
Jérôme
J
Peuchmaur
Michel
M
Valent
Alexander
A
Plantaz
Dominique
D
Rubie
Hervé
H
Valteau-Couanet
Dominique
D
Thomas
Caroline
C
Combaret
Valérie
V
Rousseau
Raphaël
R
Eggert
Angelika
A
Michon
Jean
J
Speleman
Frank
F
Delattre
Olivier
O
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
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm