COMPREHENSIVE WHOLE GENOME SEQUENCING UNRAVELS THE COMPLEX GENOMIC LANDSCAPE OF NEUROBLASTOMA

Neuroblastoma (NBL) is a clinically and biologically heterogeneous pediatric malignancy characterized by a broad spectrum of clinical outcomes. Although the genome of this tumor has been extensively studied through the last decades, a comprehensive analysis of NBL mutational landscape – which may expain its complexity – is still lacking. Moreover, while the role of germline variants in the predisposition of NBL is well established, little is known about their contribution to the onset of specific tumor phenotypes. In this dissertation we used publicly available Whole Genome Sequencing data from two NBL databases i) to provide a full compendium of NBL genomic alterations (point mutations and structural variants or SVs) and ii) to investigate the correlation between germline Small Nucleotide Variants (SNVs) and the genomic instability of NBL, a well-established marker of poor prognosis. We found unreported pathogenetic point mutations in 3 cancer-related genes, ESR1, MYH9 and SKI, the latter under-expressed in high-risk tumors. Focal and numerical copy number alterations associated with high and low risk tumors, respectively. Genomic rearrangement analysis revealed novel and recurrent translocations. Patients carrying at least one SV showed different tumor phenotypes in terms of genetic instability, mutational patterns and gene expression with respect to those without SVs. Finally, these patients also carried germline pathogenic variants in genes involved in double-strand break DNA repair. The results of this dissertation may improve the clinical stratification of NBL, help the development of novel personalized therapies and finally increase the knowledge about the germline contribution of tumor phenotypes.