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Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study

Joëlle Vermeulen UGent, Katleen De Preter UGent, Arlene Naranjo, Liesbeth Vercruysse UGent, Nadine Van Roy UGent, JAN HELLEMANS UGent, Katrien Swerts UGent, Sophie Bravo, Paolo Scaruffi and Gian Paolo Tonini, et al. (2009) LANCET ONCOLOGY. 10(7). p.663-671
abstract
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. Findings 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). Interpretation 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. Funding 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
INFANTS, CADM1, SURVIVAL, GENE-EXPRESSION, BREAST-CANCER
journal title
LANCET ONCOLOGY
Lancet Oncol.
volume
10
issue
7
pages
663 - 671
Web of Science type
Article
Web of Science id
000268153500011
JCR category
ONCOLOGY
JCR impact factor
14.47 (2009)
JCR rank
5/163 (2009)
JCR quartile
1 (2009)
ISSN
1470-2045
DOI
10.1016/S1470-2045(09)70154-8
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
849985
handle
http://hdl.handle.net/1854/LU-849985
date created
2010-02-02 16:48:59
date last changed
2010-07-29 14:25:06
@article{849985,
  abstract     = {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.
Findings 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{\textlangle}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).
Interpretation 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.
Funding 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.},
  author       = {Vermeulen, Jo{\"e}lle and De Preter, Katleen and Naranjo, Arlene and Vercruysse, Liesbeth and Van Roy, Nadine and HELLEMANS, JAN and Swerts, Katrien and Bravo, Sophie and Scaruffi, Paolo and Tonini, Gian Paolo and De Bernardi, Bruno and Noguera, Rosa and Piqueras, Marta and Canete, Adela and Castel, Victoria and Janoueix-Lerosey, Isobelle and Delattre, Olivier and Schleiermacher, Gudrun and Michon, Jean and Combaret, Valreie and Fischer, Matthias and Oberthuer, Andre and Ambros, Peter F and Beiske, Klaus and Benard, Jean and Marques, Barbara and Rubie, Herve and Kohler, Janice and Potschger, Ulrike and Ladenstein, Ruth and Hogarty, Michael D and McGrady, Patrick and London, Wendy B and Laureys, Genevieve and Speleman, Franki and Vandesompele, Jo},
  issn         = {1470-2045},
  journal      = {LANCET ONCOLOGY},
  keyword      = {INFANTS,CADM1,SURVIVAL,GENE-EXPRESSION,BREAST-CANCER},
  language     = {eng},
  number       = {7},
  pages        = {663--671},
  title        = {Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study},
  url          = {http://dx.doi.org/10.1016/S1470-2045(09)70154-8},
  volume       = {10},
  year         = {2009},
}

Chicago
Vermeulen, Joëlle, Katleen De Preter, Arlene Naranjo, Liesbeth Vercruysse, Nadine Van Roy, JAN HELLEMANS, Katrien Swerts, et al. 2009. “Predicting Outcomes for Children with Neuroblastoma Using a Multigene-expression Signature: a Retrospective SIOPEN/COG/GPOH Study.” Lancet Oncology 10 (7): 663–671.
APA
Vermeulen, Joëlle, De Preter, K., Naranjo, A., Vercruysse, L., Van Roy, N., HELLEMANS, J., Swerts, K., et al. (2009). Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. LANCET ONCOLOGY, 10(7), 663–671.
Vancouver
1.
Vermeulen J, De Preter K, Naranjo A, Vercruysse L, Van Roy N, HELLEMANS J, et al. Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. LANCET ONCOLOGY. 2009;10(7):663–71.
MLA
Vermeulen, Joëlle, Katleen De Preter, Arlene Naranjo, et al. “Predicting Outcomes for Children with Neuroblastoma Using a Multigene-expression Signature: a Retrospective SIOPEN/COG/GPOH Study.” LANCET ONCOLOGY 10.7 (2009): 663–671. Print.