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Abstract
PURPOSEWhole-genome profiles of the epigenetic modification 5-hydroxymethylcytosine (5-hmC) are robust diagnostic biomarkers in adult patients with cancer. We investigated if 5-hmC profiles would serve as novel prognostic markers in neuroblastoma, a clinically heterogeneous pediatric cancer. Because this DNA modification facilitates active gene expression, we hypothesized that 5-hmC profiles would identify transcriptomic networks driving the clinical behavior of neuroblastoma.PATIENTS AND METHODSNano-hmC-Seal sequencing was performed on DNA from Discovery (n = 51), Validation (n = 38), and Children’s Oncology Group (n = 20) cohorts of neuroblastoma tumors. RNA was isolated from 48 tumors for RNA sequencing. Genes with differential 5-hmC or expression between clusters were identified using DESeq2. A 5-hmC model predicting outcome in high-risk patients was established using linear discriminant analysis.RESULTSComparison of low- versus high-risk tumors in the Discovery cohort revealed 577 genes with differential 5-hmC. Hierarchical clustering of tumors from the Discovery and Validation cohorts using these genes identified two main clusters highly associated with established prognostic markers, clinical risk group, and outcome. Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster. The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children’s Oncology Group cohorts (hazard ratio, 3.8).CONCLUSION5-hmC profiles may be optimal DNA-based biomarkers in neuroblastoma. Analysis of transcriptional networks regulated by these epigenomic modifications may lead to a deeper understanding of drivers of neuroblastoma phenotype.
Highlights
The epigenetic modification 5-methylcytosine creates a repressed chromatin environment and decreased gene expression, elevated 5-hydroxymethylcytosine (5hmC) deposition across the gene body facilitates active transcription.[1]
Genes with increased 5-hmC and expression in the favorable cluster were enriched for pathways of neuronal differentiation and KRAS activation, whereas genes involved in inflammation and the PRC2 complex were identified in the unfavorable cluster
The linear discriminant analysis model trained on high-risk Discovery cohort tumors was prognostic of outcome when applied to high-risk tumors from the Validation and Children’s Oncology Group cohorts
Summary
Analysis of the 16 HR and 24 LR tumors from the Discovery cohort identified 577 unique genes with differential 5-hmC between risk groups (Data Supplement). Genes with elevated 5-hmC in cluster 1, compared with cluster 2 tumors, showed enrichment for gene ontology (GO) pathways of neuronal differentiation, similar to prior analysis of genes expressed in LR tumors.[28] identified were oncogenic signatures of activated KRAS signaling and suppression of BMI1 and MEL18, integral components of the polycomb repressive complex 1 (PRC1). Cluster 2 tumors were enriched for GO pathways of embryo development and morphogenesis and oncogenic signatures including activation of IL-2, IL-15, and the PRC2 complex (Fig 4C and 4D).
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