Genetic Predisposition

Neuroblastoma is a heterogeneous cancer thought to arise as a result of aberrant sympathetic nervous system development. Over the past decade, the genetic determinants of this complex disease have come into focus. Approximately 1–2% of neuroblastomas are inherited in an autosomal dominant fashion with incomplete penetrance; termed familial neuroblastoma. A combination of co-morbidity and linkage studies have identified PHOX2B and ALK as the major familial neuroblastoma predisposition genes. The genetic basis of the 98–99% of cases without a family history, termed “sporadic” neuroblastoma, has been studied through a combination of genome-wide association study (GWAS) and next-generation sequencing (NGS). GWAS efforts have led to the identification of over a dozen neuroblastoma-associated genetic loci harboring common variants with modest effect sizes and genes associated with disease susceptibility and also tumor aggressiveness. More recently, sequencing studies of germline DNA obtained from children diagnosed with neuroblastoma have revealed rare variants in known cancer predisposition genes that may contribute to neuroblastoma susceptibility and are predicted to have larger effect size. Collectively, studies of familial and sporadic neuroblastoma have provided substantial insights into tumorigenesis and revealed oncogenic vulnerabilities that are being exploited therapeutically. This chapter reviews our current understanding of neuroblastoma genetic predisposition and discusses ongoing efforts aimed at addressing gaps in our knowledge regarding this enigmatic malignancy.