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.

The prognostic roles of and correlation betweenALKandMYCNprotein expression in neuroblastoma

“…Like other embryonal malignancies, neuroblastoma is thought to be primarily a genetic disease which can be divided into familiar or sporadic with ~1%–2% of cases are inherited 31. The first significant insight into the genomic lesions driving the development of neuroblastoma was the observation in the middle of 1980 that amplification of the MYCN oncogene in neuroblastoma is associated with clinically aggressive disease and poor prognosis 6 7 31. In 2008, a large genetic linkage study in families with neuroblastoma identified a linkage signal at chromosome 2p23–24.…”

LMO1 Gene Polymorphisms Reduce Neuroblastoma Risk in Eastern Chinese Children: A Three-Center Case-Control Study

“…Neuroblastoma is genetically heterogeneous ( 8 ). Lately, intensive research has led to dramatic discoveries of some causal heritable mutations in familial neuroblastoma ( 9 ).…”

Genetic Predisposition to Neuroblastoma

“…Together, these findings raise the fundamental question of why some children develop neuroblastoma, and what predisposing genetic factors may be present in these patients. Due to the inherent limitations of candidate gene and family association studies, this question could not be addressed until the development of genotyping arrays and high-performance computing allowed researchers to conduct Genome-wide association studies (GWAS) to identify germline genetic variation that may lead to development of neuroblastoma [ 83 ]. A summary of germline GWAS variants predisposing to neuroblastoma can be seen in Table 2 .…”