Genetic susceptibility to neuroblastoma

Abstract

Until recently, the genetic basis of neuroblastoma, a heterogeneous neoplasm arising from the developing sympathetic nervous system, remained undefined. The discovery of gain-of-function mutations in the ALK receptor tyrosine kinase gene as the major cause of familial neuroblastoma led to the discovery of identical somatic mutations and rapid advancement of ALK as a tractable therapeutic target. Inactivating mutations in a master regulator of neural crest development, PHOX2B, have also been identified in a subset of familial neuroblastomas. Other high penetrance susceptibility alleles likely exist, but together these heritable mutations account for less than 10% of neuroblastoma cases. A genome-wide association study of a large neuroblastoma cohort identified common and rare polymorphisms highly associated with the disease. Ongoing resequencing efforts aim to further define the genetic landscape of neuroblastoma.

Figure 1

Graphical representation of genetic predisposition to neuroblastoma. Known familial and sporadic predisposition genes have been compiled into one summary figure across multiple studies. The familial mutations are shown in the top left of the graph representing a very rare allele frequency and high effect size. GWAS-discovered variations are in the bottom right corner representing a higher allele frequency with a lower effect size. Continued sequencing efforts are likely to uncover additional rare susceptibility variants along this spectrum, of which dozens are predicted to be discovered to explain the heritability of neuroblastoma.

Figure 2

Manhattan plot of high-risk neuroblastoma GWAS results across multiple studies. Level of significance (−log₁₀ transformed p values) for each SNP along the genome in chromosomal order is plotted, and the corresponding genes are labeled. Red line: genome-wide significance threshold based on Bonferroni adjustment. Adapted from Diskin, et al. 2012.