title: Copy number variation at 1q21.1 associated with neuroblastoma.
abstract: Common copy number variations (CNVs) represent a significant source of genetic diversity, yet their influence on phenotypic variability, including disease susceptibility, remains poorly understood. To address this problem in human cancer, we performed a genome-wide association study of CNVs in the childhood cancer neuroblastoma, a disease in which single nucleotide polymorphism variations are known to influence susceptibility. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at approximately 550,000 single nucleotide polymorphisms, and performed a CNV-based test for association. We then replicated significant observations in two independent sample sets comprised of a total of 595 cases and 3,357 controls. Here we describe the identification of a common CNV at chromosome 1q21.1 associated with neuroblastoma in the discovery set, which was confirmed in both replication sets. This CNV was validated by quantitative polymerase chain reaction, fluorescent in situ hybridization and analysis of matched tumour specimens, and was shown to be heritable in an independent set of 713 cancer-free parent-offspring trios. We identified a previously unknown transcript within the CNV that showed high sequence similarity to several neuroblastoma breakpoint family (NBPF) genes and represents a new member of this gene family (NBPF23). This transcript was preferentially expressed in fetal brain and fetal sympathetic nervous tissues, and the expression level was strictly correlated with CNV state in neuroblastoma cells. These data demonstrate that inherited copy number variation at 1q21.1 is associated with neuroblastoma and implicate a previously unknown neuroblastoma breakpoint family gene in early tumorigenesis of this childhood cancer.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, USA.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Edward F
authors.initials: EF
authors.lastname: Attiyeh
authors.forename: Marci
authors.initials: M
authors.lastname: Laudenslager
authors.forename: Kristopher
authors.initials: K
authors.lastname: Bosse
authors.forename: Kristina
authors.initials: K
authors.lastname: Cole
authors.forename: Yaël P
authors.initials: YP
authors.lastname: Mossé
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.forename: Jill E
authors.initials: JE
authors.lastname: Lynch
authors.forename: Katlyn
authors.initials: K
authors.lastname: Pecor
authors.forename: Maura
authors.initials: M
authors.lastname: Diamond
authors.forename: Cynthia
authors.initials: C
authors.lastname: Winter
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Kim
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Geiger
authors.forename: Patrick W
authors.initials: PW
authors.lastname: McGrady
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.forename: Tamim H
authors.initials: TH
authors.lastname: Shaikh
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bradfield
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Eric R
authors.initials: ER
authors.lastname: Rappaport
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
mesh_terms: D002648:Child; D019457:Chromosome Breakage; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005333:Fetus / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009447:Neuroblastoma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015203:Reproducibility of Results; D044465:White People / Q000235:genetics
chemical_list: D012333:RNA, Messenger