Abstract
Neuroblastoma is a pediatric cancer arising from sympathetic nervous system. Remarkable heterogeneity in outcomes is one of its widely known features. One of the traits strongly associated with the unfavorable subtype is the amplification of oncogene MYCN. Here, we performed cross-platform biomarker detection by comparing gene expression and pathway activation patterns from the two literature reports and from our experimental dataset, combining profiles for the 761 neuroblastoma patients with known MYCN amplification status. We identified 109 / 25 gene expression / pathway activation biomarkers strongly linked with the MYCN amplification. The marker genes/pathways are involved in the processes of purine nucleotide biosynthesis, ATP-binding, tetrahydrofolate metabolism, building mitochondrial matrix, biosynthesis of amino acids, tRNA aminoacylation and NADP-linked oxidation-reduction processes, as well as in the tyrosine phosphatase activity, p53 signaling, cell cycle progression and the G1/S and G2/M checkpoints. To connect molecular functions of the genes involved in MYCN-amplified phenotype, we built a new molecular pathway using known intracellular protein interaction networks. The activation of this pathway was highly selective in discriminating MYCN-amplified neuroblastomas in all three datasets. Our data also suggest that the phosphoinositide 3-kinase (PI3K) inhibitors may provide new opportunities for the treatment of the MYCN-amplified neuroblastoma subtype.
Highlights
Neuroblastoma arises from sympathetic nervous system embryonal crest cells localized in sympathetic ganglia and adrenal medulla
We compared the mRNA expression data obtained for the neuroblastoma samples with known status of MYCN amplification in the three different studies, using the three alternative microarray platforms
Based on the marker genes coincided in both studies and using the OncoFinder molecular interactions network, we created a new molecular pathway specific to MYCN amplification
Summary
Neuroblastoma arises from sympathetic nervous system embryonal crest cells localized in sympathetic ganglia and adrenal medulla. Despite recent survival rate improvements [6, 7], treatment of high-risk and late-stage neuroblastoma cases is still challenging due to the heterogeneity of the disease [8] and existence of treatment-resistant subgroups associated with high lethality [9]. Numerous clinical features such as age, chromosomal abnormalities, histopathological features, tumor ploidy and MYCN-amplification are used to assess the risk group and prognosis. MYCN-amplified cases are generally stratified into high-risk subgroup and are treated with multimodal cancer therapy including chemotherapy, surgery, radiotherapy, cis-retinoic acid and immunotherapy. Novel target treatment strategies are required to reduce toxicity and improve effectiveness of unfavorable subtype and late-stage NBL therapy
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