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Oncotarget. 2017 Jul 28;8(48):83768-83780. doi: 10.18632/oncotarget.19662. eCollection 2017 Oct 13.

Gene expression and molecular pathway activation signatures of MYCN-amplified neuroblastomas.

Author information

1
D. Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
2
First Oncology Research and Advisory Center, Moscow, Russia.
3
Moscow Institute of Physics and Technology, Moscow, Russia.
4
V.A. Trapeznikov Institute of Control Sciences, Russian Academy of Sciences, Moscow, Russia.
5
Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
6
Department of Oncology, Hematology and Radiology, N.I.Pirogov Russian National Research Medical University, Moscow, Russia.
7
National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
8
Pathway Pharmaceuticals, Hong Kong, China.
9
Centre for Biogerontology and Regenerative Medicine, IC Skolkovo, Moscow, Russia.
10
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Mosow, Russia.
11
Moscow State University, Faculty of Fundamental Medicine, Moscow, Russia.
12
Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
13
Federal State Budgetary Educational Institution of Further Professional Education "Russian Medical Academy of Continuous Professional Education" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.

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.

KEYWORDS:

MYCN-amplification; gene expression; neuroblastoma; pediatric; signaling pathways

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interests.

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