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DNA methylation changes at CpG and non-CpG sites are associated with development and clinical behavior in neuroblastoma [gene expression]

ABSTRACT: DNA methylation changes in neuroblastoma, a clinically-heterogeneous pediatric tumor, have been described essentially in promoter regions. We analyzed the DNA methylome of neuroblastoma using high-density microarrays and observed differential methylation not only in promoters but also in intragenic and intergenic regions at both CpG and non-CpG sites. These epigenetic changes showed a non-random distribution relative functional chromatin domains, and targeted development and cancer-related genes, relevant for neuroblastoma pathogenesis. CCND1, a gene overexpressed in neuroblastoma, showed hypomethylation of gene-body and upstream regulatory regions. Furthermore, tumors with diverse clinical-risk showed clear differences affecting CpG and, remarkably, non-CpG sites. Non-CpG methylation was present in clinically-favorable tumors and affected genes such as ALK, where non-CpG methylation correlated with low gene expression. Finally, we identified CpG and non-CpG methylation signatures which correlated with patient’s age at time-points relevant for neuroblastoma clinical behavior, and targeted genes related to neural development and neural crest regulatory network We report on the first DNA methylomes of neuroblastoma tumors using high-density microarrays. DNA methylation changes in this pediatric tumor affected both CpG and non-CpG sites associated with developmental and cancer-related genes such as CCND1 and ALK. Our study also provides new insights into the molecular basis of the heterogeneous clinical behavior of neuroblastoma. Overall design: RNA from 20 neuroblastoma tumor and 4 non patological tissues (2 fetal brain and 2 adrenal gland) samples were hybridised to the Affymetrix Human Genome U219- 24array plate.

INSTRUMENT(S): [HG-U219] Affymetrix Human Genome U219 Array

SUBMITTER: Cinzia Lavarino  

PROVIDER: GSE54720 | GEO | 2015-06-03



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<h4>Aim</h4>To define the DNA methylation landscape of neuroblastoma and its clinicopathological impact.<h4>Materials & methods</h4>Microarray DNA methylation data were analyzed and associated with functional/regulatory genome annotation data, transcriptional profiles and clinicobiological parameters.<h4>Results</h4>DNA methylation changes in neuroblastoma affect not only promoters but also intragenic and intergenic regions at cytosine-phosphate-guanine (CpG) and non-CpG sites, and target functi  ...[more]

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