Neuroblastoma, a common childhood tumour, originates from the sympathetic nervous system. Neuroblastoma is well known for its diverse clinical behaviour, ranging from spontaneous regression or maturation to aggressive metastatic disease. Neuroblastoma biology is complex and heterogeneous. The identification of genetic changes and clinical variables that are highly predictive of outcome has facilitated stratification of patients into prognostic subsets and allowed delivery of risk‐adapted therapies. Next‐generation sequencing has revealed very low frequency of somatic mutations at diagnosis, with ALK, ATRX and ARID1a/1b being the three most common mutations. To date, no single oncogene or tumour suppressor gene has been identified to be altered in the majority of neuroblastoma tumours and the key events that govern neuroblastoma initiation, differentiation or progression remain elusive. The ultimate goal for the care of children with neuroblastoma is to provide individualised assessment and therapies based on the genetic variables of both the patient and the tumour.

Key Concepts

  • Neuroblastoma has diverse clinical behaviour and heterogeneous biology.
  • Amplification of the MYCN gene in neuroblastoma is prototypic for recurrent amplification of a proto‐oncogene in human cancers.
  • Both germline and somatic ALK mutations are present in neuroblastoma.
  • TERT rearrangement and ATRX aberration confer a poor outcome in high‐risk neuroblastoma.
  • Specific genetic changes, such as MYCN amplification, or loss of heterozygosity of 1p or 11q are highly predictive of poor prognosis.
  • Neuroblastoma treatment involves risk‐adapted therapy, where patients are stratified into risk groups based on both clinical variables and tumour biology, and the goal of current treatment strategies is to use these prognostic factors to decrease the intensity of therapy delivered to low‐ and intermediate‐risk patients.
  • The current International Neuroblastoma Risk Group (INRG) Staging System utilises age, disease stage, tumour histology, MYCN status, DNA ploidy and aberrations of chromosome 11q to assign pre‐treatment risk groups.
  • DNA copy number alterations of primary tumours allow the identification of two subgroups: (1) whole chromosome gains that result in hyperdiploidy are usually present in favourable prognosis tumours and (2) segmental chromosomal aberrations (e.g. 11q LOH) are usually associated with poor prognosis tumours.
  • Immunotherapy with anti‐GD2 antibody and cytokines following stem cell transplant has led to the first major improvement in survival for patients with high‐risk neuroblastoma in the past two decades.

Keywords: neuroblastoma; neoplasm; paediatric; risk group; genetics; MYCN; ALK; ATRX; immunotherapy

Figure 1. Event‐free survival (EFS) based on Children's Oncology Group (COG) risk stratification. Children enrolled onto the Children's Cancer Group and Pediatric Oncology Group studies (1990–2010) and COG ANBL00B1 (since 2001) were classified as low, intermediate and high risk based on clinical and biologic factors (age, INSS stage, MYCN status, DNA ploidy and histology). Reproduced with permission from Park et al. © John Wiley and Sons.
Figure 2. MYCN amplification: FISH (fluorescence in situ hybridisation) using a probe to MYCN (labelled with red fluorescence) demonstrates high levels of MYCN in the nuclei of tumour cells (nuclei are counterstained in blue). MYCN amplification is defined by INRG as greater than 10 copies per cell. Courtesy of Dr. Mary Shago, Cytogenetics Laboratory, Hospital for Sick Children, Toronto, Ontario.


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Further Reading

Bosse KR and Maris JM (2016) Advances in the translational genomics of neuroblastoma: from improving risk stratification and revealing novel biology to identifying actionable genomic alterations. Cancer 122 (1): 20–33.

Pinto NR, Applebaum MA, Volchenboum SL, et al. (2015) Advances in risk classification and treatment strategies for neuroblastoma. Journal of Clinical Oncology 33 (27): 3008–3017.

Schleiermacher G, Janoueix‐Lerosey I, Ribeiro A, et al. (2010) Accumulation of segmental alterations determines progression in neuroblastoma. Journal of Clinical Oncology 28 (19): 3122–3130.

Vermeulen J, De Preter K, Naranjo A, et al. (2010) Predicting outcomes for children with neuroblastoma using a multigene‐expression signature: a retrospective SIOPEN/COG/GPOH study. Lancet Oncology 10 (7): 663–671.

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Lau, Loretta MS, and Irwin, Meredith S(Mar 2017) Neuroblastoma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006054.pub3]