Copy number variation at 1q21.1 associated with neuroblastoma.
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.
Diskin
Sharon J
SJ
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, USA.
Hou
Cuiping
C
Glessner
Joseph T
JT
Attiyeh
Edward F
EF
Laudenslager
Marci
M
Bosse
Kristopher
K
Cole
Kristina
K
Mossé
Yaël P
YP
Wood
Andrew
A
Lynch
Jill E
JE
Pecor
Katlyn
K
Diamond
Maura
M
Winter
Cynthia
C
Wang
Kai
K
Kim
Cecilia
C
Geiger
Elizabeth A
EA
McGrady
Patrick W
PW
Blakemore
Alexandra I F
AI
London
Wendy B
WB
Shaikh
Tamim H
TH
Bradfield
Jonathan
J
Grant
Struan F A
SF
Li
Hongzhe
H
Devoto
Marcella
M
Rappaport
Eric R
ER
Hakonarson
Hakon
H
Maris
John M
JM
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
D012333:RNA, Messenger