Molecular Basis and Clinical Features of Neuroblastoma

Abstract

Neuroblastoma, a neoplasm of the sympathetic nervous system, originates from neuroblastoma stem cells during embryogenesis. It exhibits unique clinical features including a tendency for spontaneous regression of tumors in infants and a high frequency of metastatic disease at diagnosis in patients aged over 18 months. Genetic risk factors and epigenetic dysregulation also play a significant role in the development of neuroblastoma. Over the past decade, our understanding of this disease has advanced considerably. This has included the identification of chromosomal copy number aberrations specific to neuroblastoma development, risk groups, and disease stage. However, high-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. New therapeutic approaches have been developed, either as alternatives to conventional chemotherapy or in combination, to overcome the dismal prognosis. Particularly promising strategies are targeted therapies that directly affect cancer cells or cancer stem cells while exhibiting minimal effect on healthy cells. This review summarizes our understanding of neuroblastoma biology and prognostic features and focuses on novel therapeutic strategies for this intractable disease.

Keywords: MYCN; anaplastic lymphoma kinase (ALK); chromosomal copy number alterations; neuroblastoma; spontaneous regression.

Figure 1.

Clinical presentation of neuroblastoma. (a) Localized thoracic neuroblastoma. The arrow indicates tumor mass. (b) Enhanced abdominal computed tomography. The arrow indicates a large tumor in the adrenal medulla. (c), Metastatic neuroblastoma revealed by metaiodobenzylguanidine (MIBG) scintigraphy.

Figure 2.

Summary of Noradrenergic (ADRN)-type and Mesenchymal (MES)-type neuroblastoma. (Cited and modified from van Groningen T, Koster J, Valentijn LJ, et al. Neuroblastoma is composed of two super-enhancer-associated differentiation states. Nat Genet. 2017;49(8):1261-6 . Copyright of the figure belongs to the authors.) Neuroblastoma was classified into Noradrenergic (ADRN)-type and Mesenchymal (MES)-type based on the superenhancer landscape of neuroblastoma. Commonly expressed genes during the course of neural crest differentiation and genetic abnormalities for each type are shown.

Figure 3.

Copy number changes in primary neuroblastoma cases. Overview of copy number changes and allelic imbalances detected using a single nucleotide polymorphism array in 215 primary neuroblastoma cases. CN; copy number, UPD; uniparental disomy, LOH; loss of heterozygosity. Neuroblastoma patients were classified by the international neuroblastoma staging system (INSS).

Figure 4.

ALK mutations detected in neuroblastoma. (Cited and modified from Mosse YP, Laudenslager M, Longo L, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008;455(7215):930-5 and Uryu K, Nishimura R, Kataoka K, et al. Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis. Oncotarget. 2017;8(64):107513-29 . Copyright of the figure belongs to the authors.) a. COSMIC frequencies of ALK mutations in neuroblastoma from the published literature with functional and therapeutic significance are shown. A blue circle indicates a missense mutation and a green circle indicates a silent mutation. The numbers in the circles represent the reported mutation numbers. The blue box indicates MAM domains and the pink box indicates the tyrosine kinase domain. b. Recurrent copy number (CN) gains in the 2p arm are defined by the MYCN locus on 2p24.3 and the ALK locus on 2p23, where vertical lines indicate common CN gains. High-grade amplifications are drawn in light red whereas simple gains are represented in dark red. c. Kinase activity of ALK mutants determined by in vitro kinase assays using the synthetic YFF peptide as a substrate.