Accumulation of segmental alterations determines progression in neuroblastoma.
OBJECTIVE
Neuroblastoma is characterized by two distinct types of genetic profiles, consisting of either numerical or segmental chromosome alterations. The latter are associated with a higher risk of relapse, even when occurring together with numerical alterations. We explored the role of segmental alterations in tumor progression and the possibility of evolution from indolent to aggressive genomic types.


METHODS
Array-based comparative genomic hybridization data of 394 neuroblastoma samples were analyzed and linked to clinical data.


RESULTS
Integration of ploidy and genomic data indicated that pseudotriploid tumors with mixed numerical and segmental profiles may be derived from pseudotriploid tumors with numerical alterations only. This was confirmed by the analysis of paired samples, at diagnosis and at relapse, as in tumors with a purely numerical profile at diagnosis additional segmental alterations at relapse were frequently observed. New segmental alterations at relapse were also seen in patients with segmental alterations at diagnosis. This was not linked to secondary effects of cytotoxic treatments since it occurred even in patients treated with surgery alone. A higher number of chromosome breakpoints were correlated with advanced age at diagnosis, advanced stage of disease, with a higher risk of relapse, and a poorer outcome.


CONCLUSIONS
These data provide further evidence of the role of segmental alterations, suggesting that tumor progression is linked to the accumulation of segmental alterations in neuroblastoma. This possibility of genomic evolution should be taken into account in treatment strategies of low- and intermediate-risk neuroblastoma and should warrant biologic reinvestigation at the time of relapse.
L'Institut National de la Santé et de la Recherche Médicale U830, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Gudrun
G
Schleiermacher
Isabelle
I
Janoueix-Lerosey
Agnès
A
Ribeiro
Jerzy
J
Klijanienko
Jérôme
J
Couturier
Gaëlle
G
Pierron
Véronique
V
Mosseri
Alexander
A
Valent
Nathalie
N
Auger
Dominique
D
Plantaz
Hervé
H
Rubie
Dominique
D
Valteau-Couanet
Franck
F
Bourdeaut
Valérie
V
Combaret
Christophe
C
Bergeron
Jean
J
Michon
Olivier
O
Delattre
D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization / Q000379:methods*; D018450:Disease Progression; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis