Hypoxia Predicts Poor Prognosis in Neuroblastoma Patients and Associates with Biological Mechanisms Involved in Telomerase Activation and Tumor Microenvironment Reprogramming

The biological and clinical heterogeneity of neuroblastoma (NB) demands novel biomarkersand therapeutic targets in order to drive the most appropriate treatment for each patient. Hypoxia isa condition of low-oxygen tension occurring in poorly vascularized tumor tissues. In thisstudy, we aimed to assess the role of hypoxia in the pathogenesis of NB and at developing anew clinically relevant hypoxia-based predictor of outcome. We analyzed the gene expressionprofiles of 1882 untreated NB primary tumors collected at diagnosis and belonging to fourexisting data sets. Analyses took advantage of machine learning methods. We identified NB-hop,a seven-gene hypoxia biomarker, as a predictor of NB patient prognosis, which is able to discriminatebetween two populations of patients with unfavorable or favorable outcome on a molecularbasis. NB-hop retained its prognostic value in a multivariate model adjusted for establishedrisk factors and was able to additionally stratify clinically relevant groups of patients. Tumors withan unfavorable NB-hop expression showed a significant association with telomerase activation and ahypoxic, immunosuppressive, poorly differentiated, and apoptosis-resistant tumor microenvironment.NB-hop defines a new population of NB patients with hypoxic tumors and unfavorable prognosisand it represents a critical factor for the stratification and treatment of NB patients.