Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study.
BACKGROUND
More accurate prognostic assessment of patients with neuroblastoma is required to better inform the choice of risk-related therapy. The aim of this study is to develop and validate a gene-expression signature to improve outcome prediction.


METHODS
59 genes were selected using an innovative data-mining strategy, and were profiled in the largest neuroblastoma patient series (n=579) to date using real-time quantitative PCR starting from only 20 ng of RNA. A multigene-expression signature was built using 30 training samples, tested on 313 test samples, and subsequently validated in a blind study on an independent set of 236 tumours.


RESULTS
The signature has a performance, sensitivity, and specificity of 85.4% (95% CI 77.7-93.2), 84.4% (66.5-94.1), and 86.5% (81.1-90.6), respectively, to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor of overall survival and progression-free survival after controlling for currently used risk factors: patients with high molecular risk have a higher risk of death from disease and higher risk of relapse or progression than patients with low molecular risk (odds ratio 19.32 [95% CI 6.50-57.43] and 3.96 [1.97-7.97] for overall survival and progression-free survival, respectively, both p<0.0001). Patients at an increased risk of an adverse outcome can also be identified in the current treatment groups, showing the potential of this signature for improved clinical management. These results were confirmed in the validation study, in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, International Neuroblastoma Staging System stage, ploidy, International Neuroblastoma Pathology Classification grade of differentiation, and mitosis karyorrhexis index (odds ratios between 4.81 and 10.53 depending on the model for overall survival and 3.68 [95% CI 2.01-6.71] for progression-free survival).


CONCLUSIONS
The 59-gene expression signature is an accurate predictor of outcome in patients with neuroblastoma. The signature is an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical-risk groups. The method and signature is suitable for routine laboratory testing, and should be evaluated in prospective studies.


BACKGROUND
The Belgian Foundation Against Cancer, the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid's Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders, the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek, the Fondation Fournier Majoie pour l'Innovation, the Instituto Carlos III, the Italian Neuroblastoma Foundation, the European Community under the FP6, and the Belgian programme of Interuniversity Poles of Attraction.
Vermeulen
Joëlle
J
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
De Preter
Katleen
K
Naranjo
Arlene
A
Vercruysse
Liesbeth
L
Van Roy
Nadine
N
Hellemans
Jan
J
Swerts
Katrien
K
Bravo
Sophie
S
Scaruffi
Paola
P
Tonini
Gian Paolo
GP
De Bernardi
Bruno
B
Noguera
Rosa
R
Piqueras
Marta
M
Cañete
Adela
A
Castel
Victoria
V
Janoueix-Lerosey
Isabelle
I
Delattre
Olivier
O
Schleiermacher
Gudrun
G
Michon
Jean
J
Combaret
Valérie
V
Fischer
Matthias
M
Oberthuer
André
A
Ambros
Peter F
PF
Beiske
Klaus
K
Bénard
Jean
J
Marques
Bárbara
B
Rubie
Hervé
H
Kohler
Janice
J
Pötschger
Ulrike
U
Ladenstein
Ruth
R
Hogarty
Michael D
MD
McGrady
Patrick
P
London
Wendy B
WB
Laureys
Geneviève
G
Speleman
Frank
F
Vandesompele
Jo
J
D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D016015:Logistic Models; D015999:Multivariate Analysis; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016019:Survival Analysis
D014408:Biomarkers, Tumor