Advances in the understanding of constitutional and somatic genomic alterations in neuroblastoma

Advances in the field of genomics have led to multiple recent discoveries in the understanding of genetic predisposition and molecular pathogenesis of the childhood cancer neuroblastoma. Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for 10% of childhood cancer related mortality. The genetic etiology of rare families with hereditary neuroblastoma is now largely understood, with the majority having activating mutations in the anaplastic lymphoma kinase (ALK) gene. Genome-wide association studies have identified multiple common, low penetrance genetic polymorphisms that are associated with a predisposition to sporadic neuroblastoma, and these associations are disease phenotype specific. While many of the discoveries related to variations in the host genome that predispose to neuroblastoma are recent, there is a long and robust history of investigation of tumor cell genomics, leading to the identification of multiple biomarkers of tumor aggressiveness. Current patient risk stratification algorithms utilize key genomic features for therapy assignment. Microarray-based tumor DNA and RNA profiling techniques and next generation sequencing efforts may further refine these risk groups and identify new tractable therapeutic targets. Moving forward, integrative genomics efforts will be needed to discover how the interaction of germline genetic variations influence oncogenesis in neuroblastoma—both initiation and progression. In this review, we summarize the recent advances in the understanding of germline predisposition and molecular pathogenesis of neuroblastoma.