Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling.

A. Schramm, J. Schulte, L. Klein-Hitpass, W. Havers, H. Sieverts, B. Berwanger, H. Christiansen, P. Warnat, B. Brors, J. Eils, R. Eils, and A. Eggert. Oncogene 24 (53): 7902--7912 (November 2005)


Neuroblastoma is a common childhood tumor comprising cases with rapid disease progression as well as spontaneous regression. Although numerous prognostic factors have been identified, risk evaluation in individual patients remains difficult. To define a reliable prognostic predictor and gene signatures characteristic of biological subgroups, we performed mRNA expression profiling of 68 neuroblastomas of all stages. Expression data were analysed using support vector machines (SVM-rbf), prediction analysis of microarrays (PAM), k-nearest neighbors (k-NN) algorithms and multiple decision trees. SVM-rbf performed best of all methods, and predicted recurrence of neuroblastoma with an accuracy of 85\% (sensitivity 77\%, specificity 94\%). PAM identified a classifier of 39 genes reliably predicting outcome with an accuracy of 80\%. In comparison, conventional risk stratification based on stage, age and MYCN-status only reached a predictive accuracy of 64\%. Kaplan-Meier analysis using the PAM classifier indicated a 5-year survival of 20 versus 78\% for patients with unfavorably versus favorably predicted neuroblastomas, respectively (P = 0.0001). Significance analysis of microarrays (SAM) identified additional genes differentially expressed among subgroups. MYCN-amplification and high expression of NTRK1/TrkA demonstrated a strong association with specific gene expression patterns. Our data suggest that microarray-derived data in addition to traditional clinical factors will be useful for risk assessment and defining biological properties of neuroblastoma.

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