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Common variations in BARD1 influence susceptibility to high-risk neuroblastoma

Nature Genetics volume 41, pages 718–723 (2009)Cite this article

Abstract

We conducted a SNP-based genome-wide association study (GWAS) focused on the high-risk subset of neuroblastoma1. As our previous unbiased GWAS showed strong association of common 6p22 SNP alleles with aggressive neuroblastoma2, we restricted our analysis here to 397 high-risk cases compared to 2,043 controls. We detected new significant association of six SNPs at 2q35 within the BARD1 locus (Pallelic = 2.35 × 10−9–2.25 × 10−8). We confirmed each SNP association in a second series of 189 high-risk cases and 1,178 controls (Pallelic = 7.90 × 10−7–2.77 × 10−4). We also tested the two most significant SNPs (rs6435862, rs3768716) in two additional independent high-risk neuroblastoma case series, yielding combined allelic odds ratios of 1.68 each (P = 8.65 × 10−18 and 2.74 × 10−16, respectively). We also found significant association with known BARD1 nonsynonymous SNPs. These data show that common variation in BARD1 contributes to the etiology of the aggressive and most clinically relevant subset of human neuroblastoma.

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Figure 1: Summary of the neuroblastoma GWAS results in the discovery set restricted to the high-risk cases.
Figure 2: Regional plot of the BARD1 locus associated with high-risk neuroblastoma.

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Acknowledgements

The authors acknowledge the Children's Oncology Group for providing neuroblastoma specimens. M.C. is supported in part by Fondazione Italiana per la Ricerca sul Cancro, FIRC, and K.B. is supported by the Howard Hughes Medical Institute Research Training Fellowship. This work was supported in part by R01-CA124709 (J.M.M.), the Giulio D'Angio Endowed Chair (J.M.M.), the Alex's Lemonade Stand Foundation (J.M.M.), Andrew's Army Foundation (J.M.M.), the Rally Foundation (J.M.M.), the Evan Dunbar Foundation (J.M.M.), the Abramson Family Cancer Research Institute (J.M.M.) and the Center for Applied Genomics (H.H.) at the Joseph Stokes Research Institute.

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Authors and Affiliations

  1. Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Mario Capasso, Marcella Devoto, Struan F A Grant & Hakon Hakonarson

  2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Mario Capasso, Marcella Devoto, Edward F Attiyeh, Yael P Mosse, Sharon J Diskin, Kristina A Cole, Kristopher Bosse, Maura Diamond, Marci Laudenslager, Cynthia Winter, Struan F A Grant, Eric Rappaport, Hakon Hakonarson & John M Maris

  3. University “Federico II”, CEINGE - Biotecnologie Avanzate, Naples, Italy

    Mario Capasso

  4. Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Marcella Devoto & Hongzhe Li

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

    Marcella Devoto

  6. The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Cuiping Hou, Joseph T Glessner, Cecilia Kim, Jonathan P Bradfield, Maria Garris, Struan F A Grant & Hakon Hakonarson

  7. Division of Hematology – Oncology and Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    Shahab Asgharzadeh & Robert C Seeger

  8. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Edward F Attiyeh, Yael P Mosse, Sharon J Diskin, Kristina A Cole, Kristopher Bosse, Maura Diamond, Marci Laudenslager, Cynthia Winter, Jayanti Jagannathan, Eric Rappaport & John M Maris

  9. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK

    Richard H Scott & Nazneen Rahman

  10. School of Cancer Sciences, University of Birmingham, UK

    Carmel McConville

  11. Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, Florida, USA

    Wendy B London

  12. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    John M Maris

Authors
  1. Mario Capasso
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Contributions

M.C., M. Devoto, H.H. and J.M.M. designed the experiment and drafted the manuscript. C.H., E.F.A., Y.P.M., K.A.C., M.L., C.W., M.G., K.B., M. Diamond and C.K. performed sample collection and quality control, and the genome-wide genotyping. W.B.L. identified high-risk neuroblastoma cases and assisted in sample selection. M.C., M. Devoto, J.P.B., S.J.D., J.J., J.T.G., S.F.A.G. and H.L. analyzed SNP data and performed association analyses. J.P.B., H.H., S.F.A.G. and H.L. performed the corrections for population stratification. S.A., R.H.S., R.C.S., C.M. and N.R. performed the BARD1 replication genotyping and analyses. C.H. and E.R. performed the genotyping of potential regulatory SNPs. All authors commented on or contributed to the manuscript.

Corresponding authors

Correspondence to Marcella Devoto, Hakon Hakonarson or John M Maris.

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Supplementary Methods, Supplementary Tables 1–4 and Supplementary Figures 1 and 2 (PDF 674 kb)

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Capasso, M., Devoto, M., Hou, C. et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat Genet 41, 718–723 (2009). https://doi.org/10.1038/ng.374

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