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

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 patients age at time-points relevant for neuroblastoma clinical behavior, and targeted genes related to neural development and neural crest regulatory network

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Gómez S, Castellano G, Mayol G, Suñol M, Queiros A, Bibikova M, Nazor KL, Loring JF, Lemos I, Rodríguez E, de Torres C, Mora J, Martín-Subero JI, Lavarino C