Background:
Neuroblastoma is a childhood tumor derived from sympathetic nervous system cells. Its broad clinical spectrum ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. Known genetic aberrations only partially mirror this diversity, pointing towards epigenetic involvement in neuroblastoma pathogenesis.
Methods:
In an integrative approach, we analyzed methylomes, transcriptomes and copy number variations in 105 neuroblastomas, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro. Prognostic signatures were identified by investigating methylomes of 362 neuroblastomas via lasso penalized regression analysis.
Results:
DNA methylation patterns defined strongly divergent patient subgroups with respect to survival and clinicobiological variables including amplified MYCN. Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Further, we provide evidence for PRC2 activity and DNA methylation collaborating in ongoing repression of tumor suppressive pro-differentiation programs in high-risk neuroblastomas. Intriguingly, these programs can be effectively re-induced via combination treatment targeting the repressive effect of both PRC2 and DNA methylation in neuroblastoma cells. In addition, we identified a prognostic methylation signature that outperforms current risk stratification.
Conclusion:
Our data considerably extend the understanding of how epigenetic deregulation contributes to neuroblastoma pathogenesis and can inform novel prognostic and therapeutic development for children with unfavorable neuroblastoma.