Abstract

We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 × 10−10), 2q37.1 (rs13397985, SP140; P = 5.40 × 10−10), 6p25.3 (rs872071, IRF4; P = 1.91 × 10−20), 11q24.1 (rs735665; P = 3.78 × 10−12), 15q23 (rs7176508; P = 4.54 × 10−12) and 19q13.32 (rs11083846, PRKD2; P = 3.96 × 10−9). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & Familial chronic lymphocytic leukemia. Semin. Oncol. 33, 195–201 (2006).

  2. 2.

    et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129, 879–890 (2007).

  3. 3.

    et al. A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia. Blood 110, 3326–3333 (2007).

  4. 4.

    & Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 34–41 (2006).

  5. 5.

    et al. Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays. Blood 109, 1202–1210 (2007).

  6. 6.

    Transcriptional control of early B cell development. Annu. Rev. Immunol. 22, 55–79 (2004).

  7. 7.

    & Germinal centres: role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8, 22–33 (2008).

  8. 8.

    & Regulation of plasma-cell development. Nat. Rev. Immunol. 5, 230–242 (2005).

  9. 9.

    , , , & Identification and characterization of a leukocyte-specific component of the nuclear body. J. Biol. Chem. 271, 29198–29204 (1996).

  10. 10.

    et al. LYSP100-associated nuclear domains (LANDs): description of a new class of subnuclear structures and their relationship to PML nuclear bodies. Blood 88, 1423–1426 (1996).

  11. 11.

    et al. Mediation of Epstein-Barr virus EBNA-LP transcriptional coactivation by Sp100. EMBO J. 24, 3565–3575 (2005).

  12. 12.

    et al. Implication of the lymphocyte-specific nuclear body protein Sp140 in an innate response to human immunodeficiency virus type 1. J. Virol. 76, 11133–11138 (2002).

  13. 13.

    et al. Loss of Bim allows precursor B cell survival but not precursor B cell differentiation in the absence of interleukin 7. J. Exp. Med. 200, 1179–1187 (2004).

  14. 14.

    et al. Immunohistochemical studies of protein kinase D (PKD) 2 expression in malignant human lymphomas. Exp. Oncol. 28, 225–230 (2006).

  15. 15.

    , , , & Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, 1848–1854 (1999).

  16. 16.

    et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, 1840–1847 (1999).

  17. 17.

    Geographical variation in the incidence of the leukemias and lymphomas. Natl. Cancer Inst. Monogr. 53, 139–142 (1979).

  18. 18.

    et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 370, 230–239 (2007).

  19. 19.

    et al. Final report of the UKCLL02 trial: A phase II study of subcutaneous alemtuzumab plus fludarabine in patients with fludarabine refractory CLL (on behalf of the NCRI CLL trials sub-group). Blood (ASH Annual Meeting Abstracts) 108, 34 (2006).

  20. 20.

    et al. Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc. Natl. Acad. Sci. USA 98, 11592–11597 (2001).

  21. 21.

    et al. Improved reliability of lymphoma diagnostics via PCR-based clonality testing: report of the BIOMED-2 Concerted Action BHM4–CT98–3936. Leukemia 21, 201–206 (2007).

  22. 22.

    Meta-analysis Decision Analysis and Cost-Effectiveness Analysis (Oxford Univ. Press, New York, 1994).

  23. 23.

    & Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

  24. 24.

    et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat. Genet. 39, 352–358 (2007).

  25. 25.

    , , & Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood 104, 1850–1854 (2004).

  26. 26.

    et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005).

  27. 27.

    et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

  28. 28.

    Wilcoxon-type test for trend. Stat. Med. 4, 87–90 (1985).

Download references

Acknowledgements

Leukaemia Research Fund (LRF) provided principal funding for the study (LRF05001 and 06002). Additional funding was provided by CLL Global Research Foundation, Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund), the Arbib fund and the European Union (CPRB LSHC-CT-2004-503465). D.C.-S. was in receipt of a PhD studentship from the Institute of Cancer Research. We are grateful to M. Yuille for input into our early work on familial CLL. This study made use of genotyping data on the 1958 Birth Cohort. Genotyping data on controls was generated and generously supplied to us by P. Deloukas of the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk. We are grateful to all investigators who contributed to the study of acute leukemia, from which phase 3 controls were drawn, to members of the ICLLLC (Supplementary Note online) and to investigators who contributed to NSCCG and GELCAPS, from which phase 1 and 2 controls were drawn. Finally, we are grateful to all the study subjects for their participation.

Author information

Author notes

    • Maria Chiara Di Bernardo
    • , Dalemari Crowther-Swanepoel
    •  & Peter Broderick

    These authors contributed equally to this work.

Affiliations

  1. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG. UK.

    • Maria Chiara Di Bernardo
    • , Dalemari Crowther-Swanepoel
    • , Peter Broderick
    • , Emily Webb
    • , Gabrielle Sellick
    • , Ruth Wild
    • , Kate Sullivan
    • , Jayaram Vijayakrishnan
    • , Yufei Wang
    • , Alan M Pittman
    •  & Richard S Houlston
  2. Northern Institute for Cancer Research, Paul O'Gorman Building, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.

    • Nicola J Sunter
    • , Andrew G Hall
    •  & James M Allan
  3. MRC Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.

    • Martin J S Dyer
  4. Section of Haemato-oncology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

    • Estella Matutes
    • , Claire Dearden
    •  & Daniel Catovsky
  5. Haematological Sciences, Leech Building, The Medical School, Newcastle University, Newcastle-upon-Tyne, UK.

    • Tryfonia Mainou-Fowler
  6. Department of Haematology, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP, UK.

    • Graham H Jackson
  7. Department of Haematology, Queen Elizabeth Hospital, Gateshead, Newcastle-upon-Tyne NE9 6SX, UK.

    • Geoffrey Summerfield
  8. Division of Haematology, University of Liverpool School of Cancer Studies, Liverpool, UK.

    • Robert J Harris
    •  & Andrew R Pettitt
  9. Department of Haematology, Leeds General Infirmary, Leeds LS1 3EX, UK.

    • Peter Hillmen
  10. Department of Haematology, Hull Royal Infirmary, Hull HU3 2JZ, UK.

    • David J Allsup
  11. Hull York Medical School and University of Hull, Hull HU16 5JQ, UK.

    • James R Bailey
  12. Department of Haematology, Birmingham Heartlands Hospital, Birmingham B9, UK.

    • Guy Pratt
  13. Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.

    • Chris Pepper
  14. Cardiff and Vale NHS Trust, Heath Park, Cardiff, CF14 4XW, UK.

    • Chris Fegan

Authors

  1. Search for Maria Chiara Di Bernardo in:

  2. Search for Dalemari Crowther-Swanepoel in:

  3. Search for Peter Broderick in:

  4. Search for Emily Webb in:

  5. Search for Gabrielle Sellick in:

  6. Search for Ruth Wild in:

  7. Search for Kate Sullivan in:

  8. Search for Jayaram Vijayakrishnan in:

  9. Search for Yufei Wang in:

  10. Search for Alan M Pittman in:

  11. Search for Nicola J Sunter in:

  12. Search for Andrew G Hall in:

  13. Search for Martin J S Dyer in:

  14. Search for Estella Matutes in:

  15. Search for Claire Dearden in:

  16. Search for Tryfonia Mainou-Fowler in:

  17. Search for Graham H Jackson in:

  18. Search for Geoffrey Summerfield in:

  19. Search for Robert J Harris in:

  20. Search for Andrew R Pettitt in:

  21. Search for Peter Hillmen in:

  22. Search for David J Allsup in:

  23. Search for James R Bailey in:

  24. Search for Guy Pratt in:

  25. Search for Chris Pepper in:

  26. Search for Chris Fegan in:

  27. Search for James M Allan in:

  28. Search for Daniel Catovsky in:

  29. Search for Richard S Houlston in:

Contributions

R.S.H. designed the study with the assistance of G.S.; R.S.H. drafted the manuscript, with substantial contributions from E.W., M.C.D.B. and D.C.-S. M.C.D.B. performed statistical analyses with contributions from E.W. and Y.W. D.C.-S., M.C.D.B. and A.M.P. performed bioinformatics analyses. Phases 1 and 2: P.B. performed laboratory management and oversaw genotyping of cases and controls; D.C.-S., K.S. and J.V. conducted sequencing; D.C.-S. conducted genotyping of cases and controls; R.S.H., G.S., D.C., E.M., C.D. and D.C.-S. developed protocols for recruitment of individuals with CLL and sample acquisition and performed sample collection of cases; members of the ICLLLC consortium carried out ascertainment of familial cases (Supplementary Note). Phase 3: J.M.A. and D.J.A. conceived of the Newcastle-based CLL study. J.M.A. established the study, supervised laboratory management and oversaw genotyping of cases and controls. N.J.S. performed sample management of cases and controls. A.G.H. developed the Newcastle Haematology Biobank, incorporating the Newcastle-based CLL study. T.M.-F., G.H.J., G.S., R.J.H., A.R.P., P.H., D.J.A., J.R.B., G.P., C.P. and C.F. developed protocols for recruitment of individuals with CLL and sample acquisition and performed sample collection of cases. All authors contributed to the final paper.

Corresponding author

Correspondence to Richard S Houlston.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Tables 1–6, Supplementary Note

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.219

Further reading