Bioinformatic analysis of the inner heterogeneity within MYCN non-amplified pediatric neuroblastoma sub-group
Abstract Background: Pediatric neuroblastoma is divided into MYCN amplified and MYCN non-amplified sub-groups. However, the extent of heterogeneity within MYCN amplified or non-amplified pediatric neuroblastoma is unclear.Methods: The prognostic significance of age and MYCN amplification was determined through multivariate cox regression and Kaplan-Meier survival analysis. MYCN non-amplified pediatric neuroblastoma patients were divided into different sub-consensuses using non-negative matrix factorization (NMF) based on the gene expression profiling. Genes particularly expressed in MYCN non-amplified young neuroblastoma patients were identified using Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. The prognostic effects of ALCAM, CACNA2D3, DST, EPB41L4A and KIFIB in MYCN non-amplified pediatric neuroblastoma patients were determined by Kaplan-Meier survival.Results: Age and MYCN amplification were independent prognostic factors in pediatric neuroblastoma. MYCN non-amplified pediatric neuroblastoma comprised young and old two distinct sub-groups. Compared with MYCN non-amplified old neuroblastoma patients, MYCN non-amplified young neuroblastoma patients had better clinical outcomes. MYCN non-amplified pediatric neuroblastoma was divided into three sub-consensuses through NMF assay and each sub-consensus was with significantly different clinical outcomes. However, MYCN amplified pediatric neuroblastoma was relatively homogeneous, and could not divide into sub-groups with different clinical outcomes by age or by NMF assay. ALCAM, CACNA2D3, DST, EPB41L4A and KIFIB were highly expressed in MYCN non-amplified young neuroblastoma patients. Moreover, the high expression levels of ALCAM, CACNA2D3, DST, EPB41L4A or KIFIB were associated with the favorable prognosis of MYCN non-amplified neuroblastoma patients. We also found that DST was an independent prognostic factor in MYCN non-amplified neuroblastoma patients and MYCN non-amplified neuroblastoma young patients with high DST expression levels had the best clinical overall survival.Conclusions: MYCN non-amplified neuroblastoma was a heterogeneous disease and could be divided into sub-groups based on age or the expression levels of ALCAM, CACNA2D3, DST, EPB41L4A or KIFIB. MYCN non-amplified neuroblastoma young patients with high DST expression levels had the best clinical overall survival.