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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 susceptibility1,2. We first genotyped 846 Caucasian neuroblastoma patients and 803 healthy Caucasian controls at 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) genes3,4 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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Figure 1: Discovery of 1q21.1 CNV associated with neuroblastoma.
Figure 2: Validation and biological relevance of 1q21.1 CNV.


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The authors acknowledge the Children’s Oncology Group (U10-CA98543) for providing neuroblastoma specimens and thank the many children who participated in this study. This work was supported in part by NIH grants T32-HG000046 (S.J.D.), R01-CA87847 (J.M.M.) and R01-CA124709, GM081519 (T.H.S.), the Giulio D’Angio Endowed Chair (J.M.M.), the Alex’s Lemonade Stand Foundation (J.M.M.), the Evan Dunbar Foundation (J.M.M.), the Rally Foundation (J.M.M.), Andrew’s Army Foundation (J.M.M.), the Abramson Family Cancer Research Institute (J.M.M.), Howard Hughes Medical Institute Medical Research Training Fellowship (K.B.) and the Center for Applied Genomics (H.H.) at the Joseph Stokes Research Institute of the Children’s Hospital of Philadelphia.

Author Contributions S.J.D. and J.M.M. designed the study and drafted the manuscript. C.H., C.K. and H.H. performed the genotyping. S.J.D. analysed SNP data and performed the CNV association study. J.B., S.F.A.G., H.H. and H.L. performed the corrections for population stratification. S.J.D., E.F.A. and Y.P.M. analysed and interpreted SNP data for tumour specimens. K.W. and S.J.D. analysed SNP data for the second replication set. J.T.G. analysed SNP data from trios for inheritance estimates. C.H., S.J.D., A.W. and E.R.R. performed and/or analysed qPCR experiments. E.A.G., K.C. and T.H.S. performed FISH experiments. S.J.D., M.L., K.B., K.P., M.D. and E.R.R. designed and/or performed experiments to identify and sequence transcript within 1q21.1 CNV. J.E.L., C.W., S.J.D. and E.R.R. performed and/or analysed expression experiments. P.W.M. and W.B.L. analysed clinical covariates. A.I.F.B. provided detailed endpoints for 1q21.1 CNV in an independent analysis of healthy controls using a custom high-resolution Agilent array. M.D., H.L. and H.H. contributed to overall GWAS study design. All authors commented on or contributed to the current manuscript.

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Correspondence to John M. Maris.

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Diskin, S., Hou, C., Glessner, J. et al. Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459, 987–991 (2009).

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