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Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia

Nature Genetics volume 41, pages 1006–1010 (2009)Cite this article

Abstract

To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 × 10−19), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 × 10−19) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 × 10−7). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.

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Figure 1: LD structure and association results for each of the disease-associated regions.
Figure 2

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Acknowledgements

Leukemia Research (UK) and the Kay Kendall Leukemia Fund provided principal funding for this study. Support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) is also acknowledged. The study made use of genotyping data obtained from the British 1958 Birth Cohort. Genotyping data on 1958 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 1958 data is available from http://www.wtccc.org.uk/. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council (MRC) grant G0000934 and the Wellcome Trust grant 068545/Z/02. We are grateful to S. Richards and J. Burrett (Clinical Trials Service Unit, Oxford), C. Harrison, L. Chilton and A. Moorman (Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University), J. Simpson (University of York), P. Thomson and A. Hussain (Cancer Immunogenetics, School of Cancer Sciences, University of Manchester) for assistance with data harmonization, and also to I. Roberts and The Children's Cancer and Leukemia Group Biological Studies Steering Group for access to MRC ALL Trial samples. P. Thomson is funded by Children with Leukemia, and we acknowledge their support. We acknowledge UK National Health Service funding to the National Institutes for Health Research Biomedical Research Centre. Finally, we are grateful to all study participants for their participation. We also thank the clinicians, other hospital staff and study staff who contributed to the blood sample and data collection for this study.

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Authors and Affiliations

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

    Elli Papaemmanuil, Fay J Hosking, Jayaram Vijayakrishnan, Amy Price, Bianca Olver & Richard S Houlston

  2. Yorkshire Regional Genetic Service, St James's University Hospital, Beckett Street, Leeds, UK

    Eammon Sheridan

  3. Department of Paediatric and Adolescent Oncology and Haematology, St James University Hospital, Leeds, UK

    Sally E Kinsey

  4. Department of Health Sciences, Epidemiology and Genetics Unit, University of York, UK

    Tracy Lightfoot & Eve Roman

  5. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    Julie A E Irving & James M Allan

  6. Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, Oxford, UK

    Ian P Tomlinson

  7. Cancer Immunogenetics Group, School of Cancer Sciences, University of Manchester, St Mary's Hospital, Manchester, UK

    Malcolm Taylor

  8. Section of Haemato-oncology, Institute of Cancer Research, Sutton, Surrey, UK

    Mel Greaves

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  1. Elli Papaemmanuil
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Contributions

R.S.H. and M.G. designed the study and obtained financial support. R.S.H. drafted the manuscript with substantial contributions from M.G. E.P. performed overall project management, development, database development and oversaw laboratory analyses; F.J.H. performed statistical analyses; F.J.H. and E.P. performed bioinformatics analyses; J.V., B.O. and A.P. performed sample preparation; E.S. and S.E.K. performed curation and sample preparation of MRC ALL 97 trial samples; T.L. and E.R. managed and maintained UKCCS sample data; M.T. performed curation and sample preparation of UKCCS samples; J.M.A. and J.A.E.I. performed ascertainment, curation and sample preparation of the Northern Institute for Cancer Research case series. I.P.T. generated and managed UK CRC control genotypes. All authors contributed to the final paper.

Corresponding author

Correspondence to Richard S Houlston.

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Supplementary Tables 1 and 2 and Supplementary Figures 1–5 (PDF 334 kb)

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Papaemmanuil, E., Hosking, F., Vijayakrishnan, J. et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41, 1006–1010 (2009). https://doi.org/10.1038/ng.430

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