FUNCTIONAL ROLE OF NON-CODING REGULATORY VARIANTS IN NEUROBLASTOMA

Emerging evidence suggests that non-coding somatic variants in cancer can contribute to disease, mainly by residing in functional regulatory regions and ultimately affecting gene expression networks. However, their interpretation is challenging. In our recent work, whole-genome sequencing (WGS) data from 151 neuroblastoma primary tumours identified two clusters of non-coding Single Nucleotide Variants (SNVs) in two distinct cis-Regulatory Elements specifically active in neuroblastoma (aCREs), denominated CTTNBP2-aCRE and MCF2L-aCRE based on their predicted target genes, respectively. Decreased expression of these genes from RNA-seq data from neuroblastoma patients correlated with poor survival and unfavourable neuroblastoma prognostic markers. The aim of this work is to functionally investigate the pathogenic effects of SNVs falling in regulatory elements, suggesting that they may cause transcriptional networks deregulation in disease pathogenesis and affect target genes expression in neuroblastoma tumorigenesis. We observed that the presence of SNVs in aCREs modulated the binding capacity of specific transcription factors, therefore altering the expression of their target genes. We suggested a potential role of these transcription factors in neuroblastoma development and a pathogenic effect of SNVs falling in their regulatory elements on gene function. This investigation also revealed that expression dysregulation of regulatory elements’ target genes may be implicated in neuroblastoma pathogenesis. Overall, our results highlight the importance of studying somatic non-coding variants in cancer and their potential impact on tumorigenic process.