Abstract
The biological and clinical heterogeneity of neuroblastoma (NB) demands novel biomarkers and therapeutic targets in order to drive the most appropriate treatment for each patient. Hypoxia is a condition of low-oxygen tension occurring in poorly vascularized tumor tissues. In this study, we aimed to assess the role of hypoxia in the pathogenesis of NB and at developing a new clinically relevant hypoxia-based predictor of outcome. We analyzed the gene expression profiles of 1882 untreated NB primary tumors collected at diagnosis and belonging to four existing 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 discriminate between two populations of patients with unfavorable or favorable outcome on a molecular basis. NB-hop retained its prognostic value in a multivariate model adjusted for established risk factors and was able to additionally stratify clinically relevant groups of patients. Tumors with an unfavorable NB-hop expression showed a significant association with telomerase activation and a hypoxic, immunosuppressive, poorly differentiated, and apoptosis-resistant tumor microenvironment. NB-hop defines a new population of NB patients with hypoxic tumors and unfavorable prognosis and it represents a critical factor for the stratification and treatment of NB patients.
Highlights
Neuroblastoma (NB) is a common extracranial solid tumor of the developing sympathetic nervous system, which accounts for roughly 5% of all diagnosed pediatric cancers [1]
We found the down-regulation of genes coding for proteins that are involved in chromatin remodeling (ARID1A and CHD5) and of the MYC gene and the up-regulation of genes involved in cell differentiation (ALK, PROM1, and RET), and coding for proteins that are involved in apoptosis and cell death (BIRC5 and TWIST1)
We reported independent evidences of the unfavorable prognostic value of hypoxia in NB and highlighted the role of hypoxia as a condition for the development and progression of NB
Summary
Neuroblastoma (NB) is a common extracranial solid tumor of the developing sympathetic nervous system, which accounts for roughly 5% of all diagnosed pediatric cancers [1]. Patients with disseminated tumors, defined as high-risk, undergo intensive treatment that includes different phases: induction based on chemotherapy at maximally tolerated doses, local treatment with surgery and radiotherapy, consolidation with high dose chemotherapy and peripheral blood stem cells rescue, maintenance based on a differentiating agent (cis-retinoic acid) and, more recently, on immunotherapy targeting the expression of disialoganglioside (GD2) on NB cells. Despite this aggressive treatment, almost 50% of high-risk NB patients are refractory to therapy, relapse, and die [1]. Efforts to identify prognostic biomarkers from the genomic interrogation of NB tumors have been made with the aim of improving patient stratification and providing novel therapeutic targets [1,2]
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