Genetic susceptibility to neuroblastoma: current knowledge and future directions
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REVIEW
Genetic susceptibility to neuroblastoma: current knowledge and future directions Laura E. Ritenour 1,2,3 & Michael P. Randall 2,3,4 & Kristopher R. Bosse 2,3,4 & Sharon J. Diskin 1,2,3,4,5 Received: 4 December 2017 / Accepted: 27 February 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018
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 Bsporadic^ 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 Neuroblastoma susceptibility . Germline . Familial neuroblastoma . Genome-wide association studies . Pediatric cancer
Introduction Laura E. Ritenour and Michael P. Randall contributed equally * Sharon J. Diskin [email protected] 1
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2
Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
3
Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
4
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
5
Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Neuroblastoma arises from aberrant neural crest development and is the most common malignancy diagnosed during the first year of life (Maris et al. 2007). This childhood cancer typically presents as abdominal, thoracic, or neck masses originating in the adrenal medulla or paraspinal sympathetic ganglia and is frequently metastatic at the time of diagnosis (Maris 2010). Neuroblastoma’s phenotypic heterog
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