Somatic Genomic Alterations in Neuroblastoma

As in many other pediatric cancer types, the genome of neuroblastoma tumors is characterized by a low mutational burden but is frequently affected by copy number alterations, often large-scale events in which (part of) a chromosome is gained or lost. Somatic mutations recurrently target ALK (around 10% of all neuroblastoma tumors at diagnosis), as well as genes of the MAPK pathway, neuritogenesis, and chromatin remodeling including ATRX and ARID genes. While specific genomic copy number alterations pinpoint the location of new, as yet hypothetical, candidate neuroblastoma driver genes, the overall pattern of copy number alterations reflects distinct underlying molecular mechanisms of neuroblastoma oncogenesis and can be used to stratify patients into risk groups. The presence of only numerical alterations in tumor cells is indicative of good prognosis, while the presence of at least one segmental chromosome alteration is associated with poor prognosis. Further efforts are currently ongoing to better differentiate patients with good and poor outcome within the current risk groups. The distinct patterns of copy number alterations in favorable versus aggressive neuroblastoma have led to the inclusion of multi-locus copy number profiling assays for the genetic work-up of neuroblastoma patients, which have evolved from hybridization-based techniques to sequencing-based methods.