Genetic susceptibility to neuroblastoma: current knowledge and future directions

• Published in: Cell and tissue research Vol. 372; no. 2; pp. 287 - 307
• Main Authors: Ritenour, Laura E., Randall, Michael P., Bosse, Kristopher R., Diskin, Sharon J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2018; Springer; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer; Children; Crizotinib; Disease susceptibility; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype & phenotype; Health aspects; Health risk assessment; Human Genetics; Humans; Infants; Malignancy; Molecular Medicine; Morbidity; Mutation; Mutation - genetics; Neoplasm Proteins - genetics; Nervous system; Neuroblastoma; Neuroblastoma - genetics; Phox2b protein; Proteomics; Review; Tumorigenesis; Familial neuroblastoma; Genome-wide association studies; Pediatric cancer; Neuroblastoma susceptibility; Germline
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-018-2820-3

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.