Background: More than fifty percent of neuroblastoma (NB) patients with adverse prognosis do not benefit from\ntreatment making the identification of new potential targets mandatory. Hypoxia is a condition of low oxygen\ntension, occurring in poorly vascularized tissues, which activates specific genes and contributes to the acquisition of\nthe tumor aggressive phenotype. We defined a gene expression signature (NB-hypo), which measures the hypoxic\nstatus of the neuroblastoma tumor. We aimed at developing a classifier predicting neuroblastoma patientsââ?¬â?¢\noutcome based on the assessment of the adverse effects of tumor hypoxia on the progression of the disease.\nMethods: Multi-layer perceptron (MLP) was trained on the expression values of the 62 probe sets constituting\nNB-hypo signature to develop a predictive model for neuroblastoma patientsââ?¬â?¢ outcome. We utilized the expression\ndata of 100 tumors in a leave-one-out analysis to select and construct the classifier and the expression data of the\nremaining 82 tumors to test the classifier performance in an external dataset. We utilized the Gene set enrichment\nanalysis (GSEA) to evaluate the enrichment of hypoxia related gene sets in patients predicted with ââ?¬Å?Poorââ?¬Â or ââ?¬Å?Goodââ?¬Â\noutcome.\nResults: We utilized the expression of the 62 probe sets of the NB-Hypo signature in 182 neuroblastoma tumors to\ndevelop a MLP classifier predicting patientsââ?¬â?¢ outcome (NB-hypo classifier). We trained and validated the classifier in\na leave-one-out cross-validation analysis on 100 tumor gene expression profiles. We externally tested the resulting\nNB-hypo classifier on an independent 82 tumorsââ?¬â?¢ set. The NB-hypo classifier predicted the patientsââ?¬â?¢ outcome with\nthe remarkable accuracy of 87 %. NB-hypo classifier prediction resulted in 2 % classification error when applied to\nclinically defined low-intermediate risk neuroblastoma patients. The prediction was 100 % accurate in assessing the\ndeath of five low/inter mediated risk patients. GSEA of tumor gene expression profile demonstrated the hypoxic\nstatus of the tumor in patients with poor prognosis.\nConclusions: We developed a robust classifier predicting neuroblastoma patientsââ?¬â?¢ outcome with a very low error\nrate and we provided independent evidence that the poor outcome patients had hypoxic tumors, supporting the\npotential of using hypoxia as target for neuroblastoma treatment.
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