Journal
NATURE
Volume 459, Issue 7249, Pages 987-U112Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08035
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Funding
- Children's Oncology Group [U10-CA98543]
- NIH [T32-HG000046, R01-CA87847, R01-CA124709, GM081519]
- Giulio D'Angio Endowed Chair
- Alex's Lemonade Stand Foundation
- Evan Dunbar Foundation
- Rally Foundation
- Andrew's Army Foundation
- Abramson Family Cancer Research Institute
- Howard Hughes Medical Institute Medical Research Training Fellowship
- Center for Applied Genomics
- Joseph Stokes Research Institute of the Children's Hospital of Philadelphia
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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(1,2). We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at similar to 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(3,4) 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.
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