Figure 1. Rare and common genomic variants predispose to neuroblastoma.

In addition to ALK and PHOX2B associated familial neuroblastoma, neuroblastoma can also arise in the setting of genetic syndromes with underlying RAS-MAPK pathway germline mutations such as NF1 in Neurofibromatosis type 1,⁹⁹ PTPN11 in Noonan syndrome,^97-98 and HRAS in Costello syndrome (left).⁹⁷ TP53 mutations associated with Li Fraumeni syndrome,¹¹⁹ EZH2 mutations associated with Weaver syndrome¹²⁰ and SDHB mutations in familial paraganglioma/pheochromocytoma (PGL/PCC)¹²¹ are also rarely associated with neuroblastoma genesis (left). Low frequency alleles in multiple DNA damage response genes (BARD1, CHEK2, PALB2, and TP53) with an intermediate effect size also contribute to neuroblastoma predisposition (middle) and more common alleles with a modest effect size discovered via a GWAS approach also collectively contribute to neuroblastoma genesis (right), and at times specifically to a high-risk (white) or low-risk (red) neuroblastoma phenotype.