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Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extra-cranial solid tumor of childhood. Neuroblastoma is a clinically heterogeneous disease, as infants with metastatic disease may experience complete tumor regression without therapy, while other children may experience relentless disease progression despite modern multimodality therapy. Current risk classification schemes use clinical, histologic, and genomic features at diagnosis to predict tumor behavior and to assign patients to an appropriate treatment regimen based on risk of recurrence. Children with lower risk disease are spared unnecessary therapies yet still achieve excellent outcomes. Nevertheless, outcome remains poor for patients classified as high risk. Additionally, survivors of high-risk neuroblastoma are at risk for significant treatment-related adverse events, emphasizing the critical need for more effective, less toxic treatments. A better understanding of the molecular pathogenesis of neuroblastoma, including an understanding of how alterations in specific biological pathways impact tumor behavior, may lead to improved treatments.


Neuroblastoma accounts for approximately 5% of childhood cancers overall, with an incidence of approximately 10 cases per 1 million children less than 15 years of age in the United States. Neuroblastoma is a disease of young children; more than one-third of patients are diagnosed during infancy, and approximately 90% are diagnosed before the age of 5 years. Neuroblastoma in adolescents and young adults is rare, and these patients present significant therapeutic challenges, as their tumors appear biologically distinct with a disease course that is often indolent, yet progressive.

The etiology of neuroblastoma is unknown in most cases, but it appears unlikely that environmental exposures play a major role. No prenatal or postnatal drug, chemical, or radiation exposure has been strongly or consistently associated with an increased risk of this disease. Neuroblastoma has been reported in patients with neurofibromatosis type 1, as well as central congenital hypoventilation syndrome (CCHS) and Hirschsprung disease, suggesting that disordered neural crest development may predispose to its development. Mutations in the PHOX2B gene, a key regulator of autonomic neural development, have been identified in patients who develop neuroblastoma in the setting of other neural crest abnormalities as well as in rare sporadic cases. Neuroblastoma has also been associated with other congenital anomalies, but a causal link has not been identified.

A familial predisposition for the development of neuroblastoma has been detected in a small subset of patients. The median age at diagnosis is younger, and multiple primary tumors are more frequently present in familial cases. Inherited mutations in PHOX2B and ALK have been identified in these pedigrees and disease penetrance is incomplete. Common genetic variants appear to contribute to disease susceptibility in the patients with sporadic (nonfamilial) disease, and some of the susceptibility variants are associated with tumor phenotype. DUSP12, HSD17B12, and DDX4-IL31RA are associated with susceptibility to low-risk neuroblastoma, whereas single nucleotide polymorphisms (SNP) within or upstream of CASC15 and CASC14, BARD1, ...

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