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Common variations in BARD1 influence susceptibility to high-risk neuroblastoma

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.

References

  1. Maris, J.M., Hogarty, M.D., Bagatell, R. & Cohn, S.L. Neuroblastoma. Lancet 369, 2106–2120 (2007).

    Article  CAS  Google Scholar 

  2. Maris, J.M. et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N. Engl. J. Med. 358, 2585–2593 (2008).

    Article  CAS  Google Scholar 

  3. Hero, B. et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J. Clin. Oncol. 26, 1504–1510 (2008).

    Article  Google Scholar 

  4. Nickerson, H.J. et al. Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J. Clin. Oncol. 18, 477–486 (2000).

    Article  CAS  Google Scholar 

  5. Matthay, K.K. et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N. Engl. J. Med. 341, 1165–1173 (1999).

    Article  CAS  Google Scholar 

  6. Berthold, F. et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol. 6, 649–658 (2005).

    Article  CAS  Google Scholar 

  7. Stacey, S.N. et al. The BARD1 Cys557Ser variant and breast cancer risk in Iceland. PLoS Med. 3, e217 (2006).

    Article  Google Scholar 

  8. Onay, V.U. et al. SNP-SNP interactions in breast cancer susceptibility. BMC Cancer 6, 114 (2006).

    Article  Google Scholar 

  9. Johnatty, S.E. et al. The BARD1 Cys557Ser polymorphism and breast cancer risk: an Australian case-control and family analysis. Breast Cancer Res. Treat. (in the press).

  10. Vahteristo, P. et al. BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition. Eur. J. Hum. Genet. 14, 167–172 (2006).

    Article  CAS  Google Scholar 

  11. Mosse, Y.P. et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455, 930–935 (2008).

    Article  CAS  Google Scholar 

  12. Wu, L.C. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat. Genet. 14, 430–440 (1996).

    Article  CAS  Google Scholar 

  13. Irminger-Finger, I. & Jefford, C.E. Is there more to BARD1 than BRCA1? Nat. Rev. Cancer 6, 382–391 (2006).

    Article  CAS  Google Scholar 

  14. Easton, D.F. et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087–1093 (2007).

    Article  CAS  Google Scholar 

  15. Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007).

    Article  CAS  Google Scholar 

  16. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  17. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  18. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  Google Scholar 

  19. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

Download references

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

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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