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

ABSTRACT: 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.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.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).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.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.

SUBMITTER: Vermeulen J

PROVIDER: S-EPMC3045079 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Vermeulen Joëlle J 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

The Lancet. Oncology 20090608 7

<h4>Background</h4>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.<h4>Methods</h4>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-expre ...[more]

PMID: 19515614

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Project description:A semiquantitative 123I-metaiodobenzylguanidine (123I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ? 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ? 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials.

Project description:BackgroundNeuroblastoma is the most common pediatric solid tumor of the sympathetic nervous system. Development of improved predictive tools for patients stratification is a crucial requirement for neuroblastoma therapy. Several studies utilized gene expression-based signatures to stratify neuroblastoma patients and demonstrated a clear advantage of adding genomic analysis to risk assessment. There is little overlapping among signatures and merging their prognostic potential would be advantageous. Here, we describe a new strategy to merge published neuroblastoma related gene signatures into a single, highly accurate, Multi-Signature Ensemble (MuSE)-classifier of neuroblastoma (NB) patients outcome.MethodsGene expression profiles of 182 neuroblastoma tumors, subdivided into three independent datasets, were used in the various phases of development and validation of neuroblastoma NB-MuSE-classifier. Thirty three signatures were evaluated for patients' outcome prediction using 22 classification algorithms each and generating 726 classifiers and prediction results. The best-performing algorithm for each signature was selected, validated on an independent dataset and the 20 signatures performing with an accuracy > = 80% were retained.ResultsWe combined the 20 predictions associated to the corresponding signatures through the selection of the best performing algorithm into a single outcome predictor. The best performance was obtained by the Decision Table algorithm that produced the NB-MuSE-classifier characterized by an external validation accuracy of 94%. Kaplan-Meier curves and log-rank test demonstrated that patients with good and poor outcome prediction by the NB-MuSE-classifier have a significantly different survival (p < 0.0001). Survival curves constructed on subgroups of patients divided on the bases of known prognostic marker suggested an excellent stratification of localized and stage 4s tumors but more data are needed to prove this point.ConclusionsThe NB-MuSE-classifier is based on an ensemble approach that merges twenty heterogeneous, neuroblastoma-related gene signatures to blend their discriminating power, rather than numeric values, into a single, highly accurate patients' outcome predictor. The novelty of our approach derives from the way to integrate the gene expression signatures, by optimally associating them with a single paradigm ultimately integrated into a single classifier. This model can be exported to other types of cancer and to diseases for which dedicated databases exist.

Project description:IntroductionBetween 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features.Materials and methodsThis SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021.ResultsOf the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant).ConclusionThis prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.

Dataset Information

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

Publications

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

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