Like many childhood cancers, neuroblastoma exhibits a paucity of recurrent somatic mutations within protein coding regions of genes in comparison with adult onset cancers. The observed paucity of recurrent somatic mutations in protein coding genes suggests that the non-coding genome, and alterations of these regions, may play important roles in childhood cancer development. However, only a relatively small number of non-coding variants have been demonstrated to promote tumorigenesis, and the contribution of noncoding RNA, such as long noncoding RNAs (lncRNAs), in cancer remains poorly understood. Therefore, we are implementing integrative (epi)genomic approaches to identify non-coding variants/mutations affecting key regulatory regions and altering transcriptional, epigenetic, or 3D architectural programs in neuroblastoma that may be exploitable for risk prediction and/or therapeutic intervention. Rationale for this approach is provided by our collaborative efforts identifying an LMO1 super-enhancer variant promoting tumor development. In addition, we and others have observed somatically acquired non-coding structural variants (SVs) upstream of the telomerase gene (TERT) in approximately 25% of high-risk neuroblastoma cases; these SVs can drive aberrant TERT expression via enhancer hijacking.