Genetic susceptibility to neuroblastoma: current knowledge and future directions

Abstract

Neuroblastoma, a malignancy of the developing peripheral nervous system that affects infants and young children, is a complex genetic disease. Over the past two decades, significant progress has been made toward understanding the genetic determinants that predispose to this often lethal childhood cancer. Approximately 1-2% of neuroblastomas are inherited in an autosomal dominant fashion and a combination of co-morbidity and linkage studies has led to the identification of germline mutations in PHOX2B and ALK as the major genetic contributors to this familial neuroblastoma subset. The genetic basis of "sporadic" neuroblastoma is being studied through a large genome-wide association study (GWAS). These efforts have led to the discovery of many common susceptibility alleles, each with modest effect size, associated with the development and progression of sporadic neuroblastoma. More recently, next-generation sequencing efforts have expanded the list of potential neuroblastoma-predisposing mutations to include rare germline variants with a predicted larger effect size. The evolving characterization of neuroblastoma's genetic basis has led to a deeper understanding of the molecular events driving tumorigenesis, more precise risk stratification and prognostics and novel therapeutic strategies. This review details the contemporary understanding of neuroblastoma's genetic predisposition, including recent advances and discusses ongoing efforts to address gaps in our knowledge regarding this malignancy's complex genetic underpinnings.

Keywords: Familial neuroblastoma; Genome-wide association studies; Germline; Neuroblastoma susceptibility; Pediatric cancer.

Fig 1. Annotated map of ALK kinase domain and kinase domain crystal structure

Mutations identified in hereditary neuroblastoma families are shown. Slate blue, NT lobe, residues 1093-1199. Grey, CT lobe, residues 1200-1399. Cyan, P-loop, residues 1123-1128. Purple, αC-helix, residues 1157-1173. Red, catalytic loop, residues 1247-1254. Orange, A-loop, residues 1270-1299. NT, N-terminus. CT, C-terminus. Crystal structure figure produced via PyMOL software (Lee et al. 2010; Chand et al. 2013; Bresler et al. 2014).

Figure 2. Frequency and effect size of neuroblastoma-associated mutations

Variants contributing to neuroblastoma risk range from rare variants of large effect to common variants of small effect. (Top left) Familial mutations in ALK and PHOX2B have been identified through linkage-based studies and evaluation of cases with associated conditions. Other rare damaging variants in cancer-associated genes have been observed in sporadic neuroblastoma by sequencing, but their true frequency and impact is unknown. Several mutations affect genes involved in DNA repair (red) and Ras-MAPK signaling (purple). (Bottom right) Common polymorphisms identified through GWAS predispose to sporadic neuroblastoma, likely through cooperative effects. These variants are plotted at the observed minor allele frequencies and odds ratios.