Fast track — ArticlesPredicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study
Introduction
Few tumours have engendered as much fascination and frustration for clinicians and scientists as neuroblastoma. This tumour is one of the most frequent solid malignancies in children and, by contrast with many other paediatric malignancies, is fatal in almost half of the patients diagnosed, despite advances in multimodal anticancer therapies. Current therapeutic stratification of patients with neuroblastoma is based on risk estimation according to combinations of age, tumour stage, MYCN status, DNA ploidy status, and histopathology.1 Clinical experience with this system suggests that the stratification of patients for treatment is useful, but patients with the same clinicopathological parameters, receiving the same treatment, can have markedly different clinical courses. As a consequence, patients with an intrinsic poor prognosis but who are classified as low risk or intermediate risk on the basis of the current stratification system, will receive inappropriately mild treatment, and this could lead to a loss of valuable time before starting the required, more intensive treatment. Alternatively, patients with an intrinsic good prognosis but recognised as high risk with the current system of stratification will undergo a toxic therapy, putting them at an unnecessary risk of long-term side-effects. Additionally, survival rates remain disappointingly low in the current high risk treatment group. Therefore, the challenge remains to identify additional tumour-specific prognostic markers for improved risk estimation at the time of diagnosis. Only then can patients receive the most appropriate therapy, be monitored more intensively if appropriate, and become eligible for new experimental therapies.
To emulate the successful identification of gene-expression signatures for other tumour types,2, 3, 4, 5 we sought to develop, validate, and implement a robust multigene-expression signature to accurately assess prognosis in children with neuroblastoma. By contrast with gene-expression studies in neuroblastoma published previously, we aimed for a high patient–gene ratio, testing a carefully selected small number of genes on a large panel of tumour samples. We further validated the signature in an independent set of tumours.
Section snippets
Patients
The initial cohort consisted of 343 patients with neuroblastoma taken from the International Society of Pediatric Oncology, European Neuroblastoma Group (SIOPEN) and from the Gesellschaft fuer Paediatrische Onkologie und Haematologie (GPOH). Patients were only included if primary untreated neuroblastoma tumour RNA (at least 60% tumour cells and confirmed histological diagnosis of neuroblastoma) was available and of sufficient quality. Almost all patients (324; 95%) were treated according to the
Results
A set of 59 genes with prognostic power in at least two independent studies was selected based on a re-analysis of seven published microarray gene-expression studies6, 7, 8, 9, 10, 11, 12 combined with an extensive screening of previously published reports for single candidate prognostic genes (table 1, webappendix). A prognostic multigene signature was subsequently built based on the expression of the 59 genes using 15 deceased high-risk and 15 low-risk patients with a long progression-free
Discussion
Identification of more specific and sensitive markers for outcome prediction and response to therapy is required to further improve the choice of risk-related therapy for children with neuroblastoma. Using a carefully selected set of 59 prognostic genes based on an innovative data-mining strategy, we did a gene-expression study on the largest neuroblastoma patient series to date, covering 579 patients in total. Our robust prognostic multigene expression signature was tested on a large set of
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