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Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk

Nature Genetics volume 42, pages 492–494 (2010)Cite this article

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Abstract

Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 × 10−11), irrespective of cell lineage.

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Figure 1: Forest plots of effect size and direction for 9p21.3 (rs3731217) association.
Figure 2: LD structure and association results for the 9p21.3 ALL locus.

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Acknowledgements

The Kay Kendall Leukemia Fund and Leukemia Research (UK) provided principal funding for the study. Support from Cancer Research UK (C1298/A8362, supported by the Bobby Moore Fund) is also acknowledged. The study made use of genotyping data from the 1958 Birth Cohort which was generated and generously supplied to us by Panagiotis Deloukas of the Wellcome Trust Sanger Institute. For a full list of the investigators who contributed to the generation of the 1958 data, see URL section. We are grateful to S. Richards and J. Burrett (Clinical Trials Service Unit, Oxford) and L. Chilton (Leukaemia Research Cytogenetics Group, Northern Institute of Cancer Research, Newcastle Univ.), J. Simpson (Univ. York), P. Thomson and A. Hussain (Cancer Immunogenetics, School of Cancer Sciences, Univ. Manchester) for assistance with data harmonization. We thank the Leukaemia Research (LR) Childhood Cancer Leukaemia Group (CCLG) Childhood Leukaemia Cell Bank for access to the Medical Research Council ALL trial samples. We are grateful to the UK Cancer Cytogenetics Group (UKCCG) for data collection and provision of samples. P. Thomson (Cancer Immunogenetics, School of Cancer Sciences, University of Manchester) is funded by Children with Leukemia and we acknowledge their support. Genotyping of German cases and controls was partly covered by funding from Tumorzentrum Heidelberg-Mannheim, EU (Food-CT-2005-016320 and Health-F3-2007-2007-200767) and Deutsche Krebshilfe. The Hungarian sample collection was financially supported by grants from the Hungarian Scientific Research Fund (T042500), the Economic Competitiveness Operational Programme, Hungary (GVOP 3.1.1-2004-05-0022/3.0) and NKTH (National Research and Technology) TECH_08-A1/2-2008-0120. M.K. is a scholar of the Fonds de la Recherche en Santé du Québec. D.S. holds the François-Karl Viau Chair in Pediatric Oncogenomics and is also a scholar of the Fonds de la Recherche en Santé du Québec. J.H. is the recipient of a National Sciences and Engineering Research Council Canada Graduate's scholarship. P. Garcia-Miguel and A. Sastre from Hospital Infantil La Paz, Madrid, and J. Luis Vivanco Martínez from Hospital 12 de Octubre, Madrid, were involved in the sample collection of the Spanish samples, and R. Alonso from Centro Nacional de Investigaciones Oncológicas was involved in the genotyping.

We are grateful to all the study subjects and individuals for their participation and, finally, we would also like to 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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Author notes

  1. Amy L Sherborne, Fay J Hosking and Richard S Houlston: These authors contributed equally to this work.

Authors and Affiliations

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

    Amy L Sherborne, Fay J Hosking, Jayaram Vijayakrishnan, Elli Papaemmanuil, Sara E Dobbins, Yussanne Ma & Richard S Houlston

  2. Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany

    Rashmi B Prasad, Rajiv Kumar, Andreas Gast & Kari Hemminki

  3. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

    Rolf Koehler & Claus R Bartram

  4. Department of Pediatrics, Acute Lymphoblastic Leukemia–Berlin-Frankfurt-Munster (ALL-BFM) Clinical Trial Center, University of Kiel, Kiel, Germany

    Martin Stanulla & Martin Schrappe

  5. Yorkshire Regional Genetic Service, St. James's University Hospital, Leeds, UK

    Eamonn Sheridan

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

    Malcolm Taylor

  7. Department of Paediatric and Adolescent Oncology and Haematology, St. James's University Hospital, Leeds, UK

    Sally E Kinsey

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

    Tracey Lightfoot & Eve Roman

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

    Julie A E Irving, James M Allan, Anthony V Moorman & Christine J Harrison

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

    Ian P Tomlinson

  11. Clinical Trial Service Unit and Epidemiological Studies Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, UK.,

    Sue Richards

  12. Department of Pediatric Hematology and Oncology, Medical School, Hannover, Germany

    Martin Zimmermann

  13. Department of Genetic, Cell- and Immunobiology, SNP Core Facility Laboratorium, Semmelweis University, Budapest, Hungary

    Csaba Szalai, Ágnes F Semsei & Daniel J Erdelyi

  14. Division of Hematology-Oncology, Research Center of the Sainte-Justine University Health Center, University of Montréal, Montréal, Quebec, Canada.,

    Maja Krajinovic, Daniel Sinnett & Jasmine Healy

  15. Spanish National Cancer Research Center (CNIO), Madrid, Spain

    Anna Gonzalez Neira

  16. Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, California, USA

    Norihiko Kawamata

  17. Regeneration Medicine of Hematopoiesis, University of Tokyo, School of Medicine, Tokyo, Japan

    Seishi Ogawa

  18. National University of Singapore Institute of Human Genetics, Singapore, Singapore

    H Phillip Koeffler

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

    Mel Greaves

Authors
  1. Amy L Sherborne
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  2. Fay J Hosking
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  15. Malcolm Taylor
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  16. Sally E Kinsey
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  17. Tracey Lightfoot
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  18. Eve Roman
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  19. Julie A E Irving
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  20. James M Allan
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  21. Anthony V Moorman
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  22. Christine J Harrison
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  23. Ian P Tomlinson
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  24. Sue Richards
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  25. Martin Zimmermann
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  26. Csaba Szalai
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  27. Ágnes F Semsei
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  29. Maja Krajinovic
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  30. Daniel Sinnett
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  31. Jasmine Healy
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  32. Anna Gonzalez Neira
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  33. Norihiko Kawamata
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  34. Seishi Ogawa
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  35. H Phillip Koeffler
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  36. Kari Hemminki
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  37. Mel Greaves
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Contributions

R.S.H. and M.G. obtained financial support. R.S.H. designed and provided overall project management. R.S.H. drafted the manuscript with contributions from F.J.H., A.L.S. and M.G.; A.L.S. performed overall project management, development, database development and oversaw laboratory analyses; F.J.H. performed statistical analyses; F.J.H. and A.L.S. performed bioinformatics analyses; J.V. and E.P. performed UK sample preparation and genotyping; E.S. and S.E.K. performed curation and sample preparation of the Medical Research Council ALL 97 trial samples; T.L. and E.R. managed and maintained UKCCS sample data; M.T. performed curation and sample preparation of United Kingdom Childhood Cancer Study 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 colorectal cancer control genotypes. A.V.M. and C.J.H. performed UK CDKN2A deletion analysis; N.K., S.O. and H.P.K. carried out German CDKN2A deletion analysis; S.E.D. and Y.M. carried out HapMap and 1000 Genomes imputation; S.R. carried out survival analysis of UK data; M.Z. carried out survival analysis of German data; K.H. oversaw analysis of the German cohort; R.B.P., A.G. and R.K. conducted genotyping of German samples; R. Koehler, M. Stanulla, M. Schrappe and C.R.B. provided German DNA for analysis; D.J.E. and C.S. coordinated the data and sample collection of the Hungarian ALL cohort; A.F.S. genotyped the Hungarian samples; M.K., D.S. and J.H. performed curation and preparation of Canadian samples; A.G.N. was responsible for curation, management and genotyping of Spanish samples. All authors contributed to the final paper.

Corresponding author

Correspondence to Richard S Houlston.

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The authors declare no competing financial interests.

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Sherborne, A., Hosking, F., Prasad, R. et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat Genet 42, 492–494 (2010). https://doi.org/10.1038/ng.585

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