Prognostic significance of MYCN related genes in pediatric neuroblastoma: a study based on TARGET and GEO datasets

Haiwei Wang,Ji Zhang,Hua Cao,Xinrui Wang,Liangpu Xu

doi:10.1186/s12887-020-02219-1

Abstract

BackgroundNeuroblastoma patients with MYCN amplification are associated with poor prognosis. However, the prognostic relevance of MYCN associated genes in neuroblastoma is unclear.MethodsThe expression profiles of MYCN associated genes were identified from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. Enriched transcription factors and signaling pathways were determined using gene set enrichment analysis (GSEA). Kaplan-Meier plotter was used to identify the prognostic relevance of MYCN associated genes. Multivariate cox regression and Spearman’s correlation were used to determine the correlation coefficients of MYCN associated genes.ResultsIn TARGET and GSE85047 datasets, neuroblastoma patients with MYCN amplification were associated with worse prognosis. Transcription factor MYC was positively associated with MYCN amplification in GSEA assay. We identified 13 MYC target genes which were increased in neuroblastoma patients with MYCN amplification in TARGET, GSE19274 and GSE85047 datasets. Moreover, six out of the 13 MYC target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL and PRMT1 were associated with adverse prognosis in TARGET and GSE85047 datasets. Transcription factor E2F1 was up-regulated by MYCN amplification and associated with the poor prognosis of neuroblastoma. Furthermore, RPS19 in ribosome signaling pathway was also associated with MYCN amplification and correlated with the poor prognosis of neuroblastoma. At last, we showed that most of MYCN target genes were correlated with each other. However, EIF4G1 was an independent prognostic marker. And the prognostic effects of the combination of MYCN amplification and EIF4G1 expression were more significant than MYCN or EIF4G1 alone.ConclusionsMYCN target genes ARMC6, DCTPP1, EIF4G1, ELOVL6, FBL, PRMT1, E2F1 and RPS19 had significant prognostic effects in pediatric neuroblastoma. And neuroblastoma patients without MYCN amplification and low EIF4G1 expression had best prognosis.

Highlights

Neuroblastoma patients with MYCN amplification are associated with poor prognosis
Prognostic significance of MYCN amplification in patients with neuroblastoma Using the clinical data deposited in Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, we analyzed the prognosis of MYCN amplification in patients with neuroblastoma
Identification of MYCN target genes in patients with neuroblastoma To reveal the functional relevance of MYCN regulated genes in neuroblastoma, we performed transcription factor enrichment analysis through gene set enrichment analysis (GSEA) assay

Summary

Introduction

Neuroblastoma patients with MYCN amplification are associated with poor prognosis. The prognostic relevance of MYCN associated genes in neuroblastoma is unclear. MYCN amplification represents the strongest independent adverse prognostic factor [9]. According to the International Neuroblastoma Risk Group, neuroblastoma patients are classified into low, intermediate or high risk subgroups based on MYCN amplification status [11]. Patients with MYCN amplification are associated with high risk and worse prognostic outcome [12]. Except MYCN amplification, MYCN protein expression [13], MYCN target gene CD44 [14] and MYCN signature [15] are used to predict the outcome of neuroblastoma. The globe MYCN amplification regulated genes and their predictive relevance in neuroblastoma are unclear

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