M. Huang2, L. Wood1, J. Taylor1, J. Zeki1, B. Chiu1 1Stanford University,Pediatric Surgery,Palo Alto, CA, USA 2Stanford University,Pediatric Hematology/Oncology,Palo Alto, CA, USA
Introduction:
Neuroblastoma is the most common pediatric extracranial solid tumor and accounts for approximately 15% of childhood cancer mortality. Despite recent treatment advances, the prognosis of high-risk neuroblastoma remains poor. By analyzing the RNA-seq data of a large primary neuroblastoma patient cohort, we aimed to identify molecular pathways and top upregulated gene signatures associated with MYCN amplification. We hypothesized that elucidation of MYCN-associated transcriptional networks with large scale of RNA-seq study can lead to identification of additional therapeutic targets.
Methods:
We used the R2 platform [Koster J. R2: Genomics Analysis and Visualization Platform (http://r2.amc.nl)], a web-based application and analyzed the Tumor Neuroblastoma-SEQC-498-seqcnb1 dataset. 498 patients are included in the database. We performed Gene Set Enrichment Analysis (GSEA) (http://www.broadinstitute.org/gsea) to interpret gene expression data between the high and low MYCN groups using the Molecular Signatures Database, MSigDB (http://www.broad.mit.edu/gsea/msigdb/index.jsp). Default parameters and weighted T-test were used. Gene sets with a false discovery rate (FDR) <25% were considered significant.
Results:
Using the C2 curated CGP (chemical and genetic perturbations, Broad Institute, 3433 gene sets), we found the following gene sets were enriched in the high MYCN subgroup of neuroblastoma, including Myc, HOXA9 and MEIS1, 'stemness' signature, and Sox-4 dependent gene set. We also identified 50 top differentially expressed genes in the high MYCN subgroup compared to those in the low MYCN subgroup, including a number of potential novel MYCN target genes and several known MYCN target genes such as PHGDH, ABCC4/MRP4, TWIST1, and TERT (Figure 1).
Conclusions:
GSEA is an unbiased approach to identify the top differentially expressed genes between MYCN amplified and non-amplified neuroblastoma tumors. The identified genes can be further analyzed to serve as potential therapeutic targets.
