Neuroblastoma is the most common solid extracranial paediatric tumour originating from the sympathetic nervous system during development. It is characterized by diverse clinical manifestations and often associated with a poor survival (40% of the children survive longer than 5 years). Only 1–2% of patients present with a family history of neuroblastoma, the vast majority of cases appear to arise sporadically. Genome-wide association studies have driven the discovery of common risk variants, but no large study has investigated the contribution of clinically relevant mutations to neuroblastoma susceptibility.
In the Italian study, published in EBioMedicine, researchers, led by Mario Capasso and Achille Iolascon, Principal Investigator of Ceinge and full professor of Medical Genetics at the University of Naples Federico II, performed exome sequencing of a large cohort of neuroblastoma cases (644) and controls (822) and used independent validation datasets to investigate the contribution of inherited rare genetic variants to neuroblastoma predisposition. They have designed two analytic approaches to identify mutations with high clinical impact in well-known cancer predisposing genes and to discover non-canonical cancer gene pathways affected by less penetrant risk mutations, demonstrating that 12% of neuroblastoma patients carry at least one clinically-relevant pathogenic variants occurring preferentially in genes belonging to the homologous recombination pathway. These inherited variants were significantly more frequent in neuroblastoma cases than in controls (6%) and many genes were validated in two independent sets of neuroblastoma cases. Mutations in RAD51C associated to neuroblastoma were reported, which advise functional studies to validate its role as candidate susceptibility gene.
The analysis also suggested a key role of genes of neurodevelopmental processes in contributing to neuroblastoma susceptibility. Indeed, gene-sets of neural tube, neuron and synapse development along with known causative-genes of neurodevelopmental disorders were enriched in rare damaging variants in neuroblastoma patients compared to controls, supporting the concept that some molecular mechanisms are shared between neuroblastoma and neurodevelopmental disorders.
The study highlights a broad spectrum of germline clinically relevant variants in a large cohort of neuroblastoma patients and indicates that inherited alterations in homologous recombination and neurodevelopmental genes can contribute to the disease initiation. Many of these variants hold potential for therapeutic actionability. Moreover, the detection of these alterations in selected neuroblastoma patients may ultimately facilitate the process of integrating genetic testing in the paediatric oncology clinic for the selection of the appropriate therapy, and expand the knowledge in cases where the genotype–phenotype association is still unclear.
