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Copy number variation at 1q21.1 associated with neuroblastoma

Nature volume 459, pages 987–991 (2009)Cite this article

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 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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Acknowledgements

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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Authors and Affiliations

  1. Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia,

    Sharon J. Diskin, Cuiping Hou, Edward F. Attiyeh, Marci Laudenslager, Kristopher Bosse, Kristina Cole, Yaël P. Mossé, Andrew Wood, Jill E. Lynch, Katlyn Pecor, Maura Diamond, Cynthia Winter, Eric R. Rappaport & John M. Maris

  2. Genomics and Computational Biology, University of Pennsylvania School of Medicine,,

    Sharon J. Diskin

  3. The Center for Applied Genomics, Children’s Hospital of Philadelphia,,

    Cuiping Hou, Joseph T. Glessner, Kai Wang, Cecilia Kim, Jonathan Bradfield, Struan F. A. Grant & Hakon Hakonarson

  4. Department of Pediatrics, University of Pennsylvania School of Medicine,

    Edward F. Attiyeh, Yaël P. Mossé, Tamim H. Shaikh, Struan F. A. Grant, Marcella Devoto, Eric R. Rappaport, Hakon Hakonarson & John M. Maris

  5. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine,,

    John M. Maris

  6. Division of Genetics, The Children’s Hospital of Philadelphia,

    Elizabeth A. Geiger, Tamim H. Shaikh, Struan F. A. Grant, Marcella Devoto & Hakon Hakonarson

  7. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA,

    Hongzhe Li & Marcella Devoto

  8. Department of Statistics, University of Florida and Children’s Oncology Group, Gainesville, Florida, 32611, USA,

    Patrick W. McGrady & Wendy B. London

  9. Genomic Medicine, Imperial College London, London, SW7 2AZ, UK ,

    Alexandra I. F. Blakemore

  10. Department of Experimental Medicine, University of Rome “La Sapienza”, Rome, 00185, Italy,

    Marcella Devoto

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Corresponding author

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). https://doi.org/10.1038/nature08035

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