Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma

Nature Genetics volume 44, pages 1126–1130 (2012)Cite this article

Subjects

Abstract

Neuroblastoma is a cancer of the sympathetic nervous system that accounts for approximately 10% of all pediatric oncology deaths1. Here, we report a genome-wide association study of 2,817 neuroblastoma cases and 7,473 controls. We identified two new associations at 6q16, the first within HACE1 (rs4336470; combined P = 2.7 × 10−11; odds ratio 1.26, 95% confidence interval (CI) 1.18–1.35) and the second within LIN28B (rs17065417; combined P = 1.2 × 10−8; odds ratio 1.38, 95% CI 1.23–1.54). Expression of LIN28B and let-7 miRNA correlated with rs17065417 genotype in neuroblastoma cell lines, and we observed significant growth inhibition upon depletion of LIN28B, specifically in neuroblastoma cells that were homozygous for the risk allele. Low HACE1 and high LIN28B expression in diagnostic primary neuroblastomas were associated with worse overall survival (P = 0.008 and 0.014, respectively). Taken together, these data show that common variants in HACE1 and LIN28B influence neuroblastoma susceptibility and indicate that both genes likely have a role in disease progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regional association plots at the HACE1 and LIN28B loci.
Figure 2: LIN28B risk alleles correlate with increased LIN28B expression and decreased let-7 miRNA expression.
Figure 3: Transient knockdown of LIN28B influences neuroblastoma cell growth in an expression-specific manner.
Figure 4: HACE1 and LIN28B expression are associated with advanced disease and poor outcome in neuroblastoma.

Similar content being viewed by others

References

  1. Maris, J.M. Recent advances in neuroblastoma. N. Engl. J. Med. 362, 2202–2211 (2010).

    Article  CAS  Google Scholar 

  2. Yu, A.L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  4. Janoueix-Lerosey, I. et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455, 967–970 (2008).

    Article  CAS  Google Scholar 

  5. Trochet, D. et al. Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. Am. J. Hum. Genet. 74, 761–764 (2004).

    Article  CAS  Google Scholar 

  6. Mosse, Y.P. et al. Germline PHOX2B mutation in hereditary neuroblastoma. Am. J. Hum. Genet. 75, 727–730 (2004).

    Article  CAS  Google Scholar 

  7. 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 

  8. Capasso, M. et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat. Genet. 41, 718–723 (2009).

    Article  CAS  Google Scholar 

  9. Wang, K. et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 469, 216–220 (2011).

    Article  CAS  Google Scholar 

  10. Nguyen, B. et al. Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility loci. PLoS Genet. 7, e1002026 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Latorre, V. et al. Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiol. Biomarkers Prev. 21, 658–663 (2012).

    Article  CAS  Google Scholar 

  13. Henderson, T.O. et al. Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children's Oncology Group study. J. Clin. Oncol. 29, 76–82 (2011).

    Article  Google Scholar 

  14. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  Google Scholar 

  15. Anglesio, M.S. et al. Differential expression of a novel ankyrin containing E3 ubiquitin-protein ligase, Hace1, in sporadic Wilms' tumor versus normal kidney. Hum. Mol. Genet. 13, 2061–2074 (2004).

    Article  CAS  Google Scholar 

  16. Hibi, K. et al. Aberrant methylation of the HACE1 gene is frequently detected in advanced colorectal cancer. Anticancer Res. 28, 1581–1584 (2008).

    CAS  PubMed  Google Scholar 

  17. Sakata, M. et al. Methylation of HACE1 in gastric carcinoma. Anticancer Res. 29, 2231–2233 (2009).

    CAS  PubMed  Google Scholar 

  18. Zhang, L. et al. The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers. Nat. Med. 13, 1060–1069 (2007).

    Article  CAS  Google Scholar 

  19. Zhao, J., Zhang, Z., Vucetic, Z., Soprano, K.J. & Soprano, D.R. HACE1: a novel repressor of RAR transcriptional activity. J. Cell. Biochem. 107, 482–493 (2009).

    Article  CAS  Google Scholar 

  20. Slade, I. et al. Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies HACE1 as a putative Wilms tumour susceptibility gene. J. Med. Genet. 47, 342–347 (2010).

    Article  CAS  Google Scholar 

  21. Piskounova, E. et al. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 147, 1066–1079 (2011).

    Article  CAS  Google Scholar 

  22. Iliopoulos, D., Hirsch, H.A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).

    Article  CAS  Google Scholar 

  23. West, J.A. et al. A role for Lin28 in primordial germ-cell development and germ-cell malignancy. Nature 460, 909–913 (2009).

    Article  CAS  Google Scholar 

  24. Viswanathan, S.R. et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat. Genet. 41, 843–848 (2009).

    Article  CAS  Google Scholar 

  25. Martinez, N.J. & Gregory, R.I. MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity. Cell Stem Cell 7, 31–35 (2010).

    Article  CAS  Google Scholar 

  26. Melton, C., Judson, R.L. & Blelloch, R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463, 621–626 (2010).

    Article  CAS  Google Scholar 

  27. Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    Article  CAS  Google Scholar 

  28. Neale, G. et al. Molecular characterization of the pediatric preclinical testing panel. Clin. Cancer Res. 14, 4572–4583 (2008).

    Article  CAS  Google Scholar 

  29. Zhu, H. et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81–94 (2011).

    Article  CAS  Google Scholar 

  30. Yuan, J., Nguyen, C.K., Liu, X., Kanellopoulou, C. & Muljo, S.A. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195–1200 (2012).

    Article  CAS  Google Scholar 

  31. Widén, E. et al. Distinct variants at LIN28B influence growth in height from birth to adulthood. Am. J. Hum. Genet. 86, 773–782 (2010).

    Article  Google Scholar 

  32. Ong, K.K. et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. 41, 729–733 (2009).

    Article  CAS  Google Scholar 

  33. Sulem, P. et al. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat. Genet. 41, 734–738 (2009).

    Article  CAS  Google Scholar 

  34. Permuth-Wey, J. et al. LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer. Cancer Res. 71, 3896–3903 (2011).

    Article  CAS  Google Scholar 

  35. Bosse, K.R. et al. Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res. 72, 2068–2078 (2012).

    Article  CAS  Google Scholar 

  36. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    Article  CAS  Google Scholar 

  37. Molenaar, J.J. et al. Copy number defects of G1-cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis. Genes Chromosomes Cancer 51, 10–19 (2012).

    Article  CAS  Google Scholar 

  38. Brodeur, G.M. et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J. Clin. Oncol. 11, 1466–1477 (1993).

    Article  CAS  Google Scholar 

  39. Shimada, H. et al. The International Neuroblastoma Pathology Classification (Shimada) System. Cancer 86, 364–372 (1999).

    Article  CAS  Google Scholar 

  40. Mathew, P. et al. Detection of MYCN gene amplification in neuroblastoma by fluorescence in situ hybridization: a Pediatric Oncology Group study. Neoplasia 3, 105–109 (2001).

    Article  CAS  Google Scholar 

  41. Look, A.T. et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J. Clin. Oncol. 9, 581–591 (1991).

    Article  CAS  Google Scholar 

  42. Gunderson, K.L., Steemers, F.J., Lee, G., Mendoza, L.G. & Chee, M.S. A genome-wide scalable SNP genotyping assay using microarray technology. Nat. Genet. 37, 549–554 (2005).

    Article  CAS  Google Scholar 

  43. Steemers, F.J. et al. Whole-genome genotyping with the single-base extension assay. Nat. Methods 3, 31–33 (2006).

    Article  CAS  Google Scholar 

  44. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  Google Scholar 

  45. Howie, B., Marchini, J. & Stephens, M. Genotype imputation with thousands of genomes. G3 (Bethesda) 1, 457–470 (2011).

    Article  Google Scholar 

  46. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  Google Scholar 

  47. Cole, K.A. et al. A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol. Cancer Res. 6, 735–742 (2008).

    Article  CAS  Google Scholar 

  48. Kaplan, E.L. & Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assn. 53, 457–481 (1958).

    Article  Google Scholar 

Download references

Acknowledgements

We thank P. Sleiman for useful discussions regarding meta-analysis using METAL. This work was supported in part by US National Institutes of Health (NIH) grants R01-CA124709 (J.M.M.), K99-CA151869 (S.J.D.), P30-HD026979 (M. Devoto) and K08-CA136979 (K.A.C.); 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 PressOn Foundation (J.M.M.); the Abramson Family Cancer Research Institute (J.M.M.); Fondazione Italiana per la Lotta al Neuroblastoma and Associazione Italiana per la Ricerca sul Cancro (M.C.); and the Center for Applied Genomics at the Children's Hospital of Philadelphia Research Institute (H.H.).

Author information

Authors and Affiliations

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

    Sharon J Diskin, Robert W Schnepp, Kristina A Cole, Edward F Attiyeh, Maura Diamond, Erica L Carpenter, Cynthia Winter, Hanna Lee, Jayanti Jagannathan & John M Maris

  2. Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Sharon J Diskin, Robert W Schnepp, Kristina A Cole, Edward F Attiyeh, Maura Diamond, Erica L Carpenter, Cynthia Winter, Hanna Lee, Jayanti Jagannathan & John M Maris

  3. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Sharon J Diskin, Kristina A Cole, Edward F Attiyeh, Hakon Hakonarson, Marcella Devoto & John M Maris

  4. Dipartimento di Biochimicae Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy

    Mario Capasso & Achille Iolascon

  5. Ceinge–Biotecnologie Avanzate, Naples, Italy

    Mario Capasso & Achille Iolascon

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

    Cuiping Hou & Hakon Hakonarson

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

    Valeria Latorre, Hakon Hakonarson & Marcella Devoto

  8. Department of Cell Biology, Università della Calabria, Rende, Italy

    Valeria Latorre

  9. Department of Molecular Medicine, University of Rome La Sapienza, Rome, Italy

    Marcella Devoto

  10. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Marcella Devoto

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

    Sharon J Diskin & John M Maris

Authors
  1. Sharon J Diskin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario Capasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert W Schnepp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kristina A Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edward F Attiyeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cuiping Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maura Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Erica L Carpenter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cynthia Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hanna Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jayanti Jagannathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Valeria Latorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Achille Iolascon
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hakon Hakonarson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marcella Devoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. John M Maris
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.J.D. and J.M.M. designed the experiment and drafted the manuscript. S.J.D. analyzed SNP data, performed SNP association studies, and analyzed mRNA and miRNA expression data. M.C. and A.I. replicated SNP associations in the Italian cohort. V.L. and M.D. replicated SNP associations in the African-American cohort. E.L.C. and H.L. confirmed LIN28B protein expression by protein blot. R.W.S. and C.W. performed experiments with siRNA-mediated knockdown of LIN28B. E.F.A. generated miRNA expression array data, including low-level summary values. K.A.C. performed RT-PCR in primary tumors. M. Diamond and C.H. organized samples and genotyped cases. J.J. participated in expression array analyses. H.H. generated and provided all control data for the GWAS. M. Devoto and H.H. contributed to overall study design. All authors commented on or contributed to the current manuscript.

Corresponding author

Correspondence to John M Maris.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–10 and Supplementary Figures 1–12 (PDF 1681 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Diskin, S., Capasso, M., Schnepp, R. et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet 44, 1126–1130 (2012). https://doi.org/10.1038/ng.2387

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2387

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing