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Neuroblastoma: biological insights into a clinical enigma

Key Points

  • Neuroblastoma is the most common extracranial tumour of childhood. This tumour originates from precursor cells of the peripheral (sympathetic) nervous system and usually arises in a paraspinal location in the abdomen or chest.

  • The aetiology of neuroblastoma is unknown, but it seems unlikely that environmental exposures are important. A subset of patients inherits a genetic predisposition to neuroblastoma, and these patients usually have multifocal primary tumours that arise at an early age. A predisposition locus has been mapped to the short arm of chromosome 16.

  • Neuroblastomas can be classified into subtypes that are predictive of clinical behaviour based on the patterns of genetic change. This information can be useful in the selection of therapy.

  • Favourable tumours are characterized by near-triploid karyotypes with whole chromosome gains. These tumours rarely have structural rearrangements, and they usually express the TrkA neurotrophin receptor. Patients with these tumours are more likely to be less than 1 year of age, have localized tumours and a good prognosis.

  • Unfavourable tumours are characterized by structural changes, including deletions of 1p or 11q, unbalanced gain of 17q and/or amplification of the MYCN protooncogene. They might also express the TrkB neurotrophin receptor and its ligand, brain-derived neurotrophic factor (BDNF). These patients are usually older than 1 year of age, have more advanced stages of disease and a much worse prognosis, even with aggressive treatment.

  • Mass screening for neuroblastoma at 6–12 months of age led to an increased prevalence of neuroblastoma detected in the screened populations, but no decrease in mortality from this disease. The tumours detected have overwhelmingly been of the favourable genetic subtype.

  • Novel, biologically based therapies are being developed that would specifically target the genes, proteins and pathways that are responsible for malignant transformation and progression in neuroblastomas. These approaches are likely to be more effective and less toxic than conventional therapy.

  • In the future, it is likely that more extensive molecular profiling of the genetic changes and expression patterns of neuroblastoma will lead to an even more precise subclassification system that will be predictive of outcome, as well as therapies to which the tumour is most likely to be responsive.

Abstract

Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous system and is the most common solid tumour in childhood. Interestingly, most infants experience complete regression of their disease with minimal therapy, even with metastatic disease. However, older patients frequently have metastatic disease that grows relentlessly, despite even the most intensive multimodality therapy. Recent advances in understanding the biology and genetics of neuroblastomas have allowed classification into low-, intermediate- and high-risk groups. This allows the most appropriate intensity of therapy to be selected — from observation alone to aggressive, multimodality therapy. Future therapies will focus increasingly on the genes and biological pathways that contribute to malignant transformation or progression.

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Figure 1: MYCN amplification in neuroblastomas.
Figure 2: Survival of infants with metastatic neuroblastoma based on MYCN status.
Figure 3: Loss of heterozygosity of chromosome 1p in neuroblastomas.
Figure 4: Signal-transduction pathway of the TrkA tyrosine kinase receptor.
Figure 5: Genetic model of neuroblastoma development.

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Acknowledgements

This work was supported in part by National Institutes of Health grants, and the Audrey E. Evans Endowed Chair. Some of this material has been published previously (see references 1–4).

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DATABASES

LocusLink

BCL2

BDNF

CD95

CDKN2A

CDKN2B

CDKN2C

HRAS

LDH

MAX

MCM7

MDM2

MDR1

MRP1

MYCL

MYCN

NF1

NGF

NRAS

NSE

NT3

NT4

ODC

p75

telomerase

TP53

TrkA

TrkB

TrkC

OMIM

neuroblastoma

von Recklinghausen disease

Glossary

PLOIDY

A general term that is used to describe the overall chromosome number of a cell. A normal diploid cell has a karyotype with 46 chromosomes and a DNA content of 1.0. A triploid cell with 69 chromosomes has a DNA content of 1.5.

ALLELIC LOSS

(or loss of heterozygosity (LOH)). If the DNA is polymorphic in the normal constitutional DNA (two alleles identified) of a patient and only one allele is present in the tumour, then there is presumptive loss of DNA at that locus. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

NEUROTROPHIN

A protein that binds to a receptor on a nerve cell, which, in turn, activates signalling pathways that support cell survival.

AUTOCRINE

A mechanism of self-activation through a ligand–receptor pathway. Autocrine activation results from a ligand that is produced by a cell binding to and activating a receptor on the same cell.

AUTOSOMAL DOMINANT

A pattern of inheritance through the non-sex chromosomes, in which a gene (allele) on one chromosome in a pair results in a phenotype and is dominant over the phenotype conferred by the other allele.

KNUDSON'S TWO-HIT HYPOTHESIS

Alfred Knudson proposed that familial cancers result from two rate-limiting mutations. One mutation is inherited in the constitutional DNA, and a single somatically acquired mutation in any cell of the target tissue could result in a tumour. In sporadic cases, both mutations are somatically acquired.

NEUROFIBROMATOSIS TYPE I

(Or von Recklinghausen disease). An autosomal-dominant disorder that is characterized by pigmented patches of skin and by the formation of neurofibromas (tumours involving nerve tissue) in the skin, subcutaneous tissue, cranial nerves and spinal root nerves.

HIRSCHSPRUNG DISEASE

A congenital condition that results from a failure to completely enervate the distal colon. This leads to obstruction of the large intestine from inadequate motility and collapse of this distal segment.

KARYOTYPE

A presentation of the chromosomes of a cell organized in pairs and by size. Normal human cells have a karyotype of 46 chromosomes (23 pairs).

SYMPATHETIC NERVOUS SYSTEM

The peripheral nervous system that is characterized by the neurotransmitter noradrenaline.

ADRENAL MEDULLA

The centre of the adrenal gland, where ganglion cells produce chemicals such as noradrenaline and adrenaline. This is a common site from which neuroblastomas originate.

PARASPINAL

Adjacent to the spine. This is a common location of sympathetic nerve cells, from which neuroblastomas arise.

NEUROBLASTS

Immature nerve cells.

SCHWANN CELLS

Cells that are derived from a group of embryonic cells called the neural crest, which are associated with and supportive of nerve cells. Schwann cells are the stromal cells in mature ganglioneuromas.

COMPARATIVE GENOMIC HYBRIDIZATION

(CGH). A technique that is used to detect chromosome gain or loss by hybridizing DNA from a target cell and a normal cell that are differentially labelled with unique fluors to a normal karyotype.

GANGLION CELLS

Mature, post-mitotic, fully differentiated nerve cells.

PARACRINE

Paracrine activation results from a ligand produced by one cell binding to and activating a receptor on an adjacent cell.

CATECHOLAMINES

Catecholamines are small molecules such as DOPA, dopamine and norepinephrine that function as neurotransmitters in the central and peripheral nervous systems. These compounds are broken down into urinary metabolites that can be measured in the urine.

PROTON-BEAM THERAPY

Radiation therapy for local tumour control using a proton beam, as opposed to an electron or photon beam (used in more conventional radiation therapy).

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Brodeur, G. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 3, 203–216 (2003). https://doi.org/10.1038/nrc1014

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