Letter | Published:

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Nature Genetics volume 46, pages 12331238 (2014) | Download Citation

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10−21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10−10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10−8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10−13 and 3.63 × 10−11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

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Acknowledgements

We thank C. Allmer, E. Angelucci, A. Bigelow, S. Buehler, K. Butterbach, A. Chabrier, J.M. Conners, M. Corines, M. Cornelis, K. Corsano, H. Dykes, L. Ershler, A. Gabbas, R.P. Gallagher, R.D. Gascoyne, P. Hui, L. Irish, L. Jacobus, L. Klareskog, A.S. Lai, J. Lunde, M. McAdams, R. Montalvan, L. Padyukov, M. Rais, T. Rattle, L. Rigacci, K. Snyder, G. Specchia, M. Stagner, G. Thomas, C. Tornow, G. Wood and M. Yang. The overall GWAS project was supported by the Intramural Program of the US National Institutes of Health/National Cancer Institute. A list of support provided to individual studies appears in the Supplementary Note.

Author information

Author notes

    • James R Cerhan
    • , Sonja I Berndt
    • , Joseph Vijai
    • , Hervé Ghesquières
    • , James McKay
    • , Sophia S Wang
    •  & Zhaoming Wang

    These authors contributed equally to this work.

    • Xifeng Wu
    • , Silvia de Sanjose
    • , Karin E Smedby
    • , Gilles Salles
    • , Christine F Skibola
    • , Nathaniel Rothman
    •  & Stephen J Chanock

    These authors jointly directed this work.

Affiliations

  1. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • James R Cerhan
    •  & Susan L Slager
  2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Sonja I Berndt
    • , Qing Lan
    • , Mark P Purdue
    • , Demetrius Albanes
    • , Patricia Hartge
    • , Lindsay M Morton
    • , Stephanie Weinstein
    • , Joshua Sampson
    • , Charles C Chung
    • , Nilanjan Chatterjee
    • , Joseph F Fraumeni Jr
    • , Nathaniel Rothman
    •  & Stephen J Chanock
  3. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Joseph Vijai
    • , Kenneth Offit
    • , Andrew Zelenetz
    • , Robert J Klein
    •  & Danylo J Villano
  4. Department of Hematology, Centre Léon Bérard, Lyon, France.

    • Hervé Ghesquières
  5. Laboratoire de Biologie Moléculaire de la Cellule, UMR 5239, CNRS, Pierre-Benite, France.

    • Hervé Ghesquières
    •  & Gilles Salles
  6. Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer, Lyon, France.

    • James McKay
  7. Department of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, California, USA.

    • Sophia S Wang
  8. Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland, USA.

    • Zhaoming Wang
    • , Meredith Yeager
    • , Laurie Burdett
    •  & Amy Hutchinson
  9. Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, Alabama, USA.

    • Lucia Conde
    • , Jacques Riby
    •  & Christine F Skibola
  10. Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, California, USA.

    • Lucia Conde
    • , Jacques Riby
    • , Martyn T Smith
    •  & Christine F Skibola
  11. Department of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
  12. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
    •  & Roel C H Vermeulen
  13. Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.

    • Alexandra Nieters
  14. Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France.

    • David Cox
    •  & Amelie S Veron
  15. Environmental Epidemiology of Cancer Group, INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France.

    • Alain Monnereau
    •  & Jacqueline Clavel
  16. UMRS 1018, Université Paris Sud, Villejuif, France.

    • Alain Monnereau
    •  & Jacqueline Clavel
  17. Registre des Hémopathies Malignes de la Gironde, Institut Bergonié, Bordeaux, France.

    • Alain Monnereau
  18. Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Christopher R Flowers
  19. Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, Pennsylvania, USA.

    • Anneclaire J De Roos
  20. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Anneclaire J De Roos
    •  & Lesley F Tinker
  21. Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.

    • Angela R Brooks-Wilson
  22. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.

    • Angela R Brooks-Wilson
  23. Human Genetics Foundation, Turin, Italy.

    • Gianluca Severi
    •  & Paolo Vineis
  24. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Gianluca Severi
    •  & Graham G Giles
  25. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Victoria, Australia.

    • Gianluca Severi
    •  & Graham G Giles
  26. Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.

    • Mads Melbye
    •  & Henrik Hjalgrim
  27. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Mads Melbye
  28. Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA.

    • Jian Gu
    • , Yuanqing Ye
    •  & Xifeng Wu
  29. Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio, USA.

    • Rebecca D Jackson
  30. Department of Health Sciences, University of York, York, UK.

    • Eleanor Kane
    • , Tracy Lightfoot
    • , Simon Crouch
    • , Alex Smith
    •  & Eve Roman
  31. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

    • Lauren R Teras
    •  & W Ryan Diver
  32. Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.

    • Claire M Vajdic
  33. Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.

    • John J Spinelli
  34. School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.

    • John J Spinelli
  35. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Rachel S Kelly
    • , Kimberly A Bertrand
    • , Hans-Olov Adami
    • , Dimitrios Trichopoulos
    • , Francine Laden
    • , Edward Giovannucci
    • , Peter Kraft
    • , Jinyan Huang
    • , Baoshan Ma
    •  & Liming Liang
  36. Medical Research Council (MRC)–Public Health England (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Rachel S Kelly
    •  & Paolo Vineis
  37. Department of Biomedical Science, University of Cagliari, Monserrato, Italy.

    • Mariagrazia Zucca
  38. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Kimberly A Bertrand
    • , Brenda M Birmann
    • , Francine Laden
    •  & Edward Giovannucci
  39. Department of Population Health, New York University School of Medicine, New York, New York, USA.

    • Anne Zeleniuch-Jacquotte
  40. Cancer Institute, New York University School of Medicine, New York, New York, USA.

    • Anne Zeleniuch-Jacquotte
  41. Health Studies Sector, Westat, Rockville, Maryland, USA.

    • Charles Lawrence
  42. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Degui Zhi
  43. Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

    • Thomas M Habermann
    • , Anne J Novak
    • , Mark Liebow
    • , Carrie A Thompson
    • , Stephen M Ansell
    •  & Thomas E Witzig
  44. Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.

    • Brian K Link
    •  & George J Weiner
  45. Department of Laboratory Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Ahmet Dogan
  46. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA.

    • Yan W Asmann
  47. Centre National de Génotypage, Evry, France.

    • Diana Zelenika
  48. Centre Heni Becquerel, Rouen, France.

    • Hervé Tilly
  49. Department of Hematology, Centre Hospitalier Universitaire (CHU) Henri Mondor, Creteil, France.

    • Corinne Haioun
  50. Department of Pathology, Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

    • Thierry Jo Molina
  51. Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.

    • Bengt Glimelius
  52. Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden.

    • Bengt Glimelius
  53. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Hans-Olov Adami
  54. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.

    • Paige M Bracci
    •  & Elizabeth A Holly
  55. Department of Preventive Medicine, University of Southern California Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Wendy Cozen
  56. Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Wendy Cozen
  57. Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, USA.

    • Richard K Severson
  58. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Kari E North
  59. Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Kari E North
  60. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Nikolaus Becker
    •  & Rudolph Kaaks
  61. Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Catala d'Oncologia, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.

    • Yolanda Benavente
    •  & Silvia de Sanjose
  62. Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.

    • Yolanda Benavente
    •  & Silvia de Sanjose
  63. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Paolo Boffetta
  64. Group of Genetic Epidemiology, Section of Genetics, International Agency for Research on Cancer, Lyon, France.

    • Paul Brennan
  65. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic.

    • Lenka Foretova
  66. Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon, France.

    • Marc Maynadie
  67. School of Nursing and Human Sciences, Dublin City University, Dublin, Ireland.

    • Anthony Staines
  68. Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA.

    • Tongzhang Zheng
    •  & Yawei Zhang
  69. Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.

    • Theodore R Holford
  70. Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.

    • Anne Kricker
  71. Pathology, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia.

    • Jenny Turner
  72. Department of Histopathology, Douglass Hanly Moir Pathology, Macquarie Park, New South Wales, Australia.

    • Jenny Turner
  73. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.

    • Melissa C Southey
  74. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Jarmo Virtamo
  75. School of Public Health, Imperial College London, London, UK.

    • Elio Riboli
  76. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.

    • Dimitrios Trichopoulos
  77. Hellenic Health Foundation, Athens, Greece.

    • Dimitrios Trichopoulos
  78. Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.

    • Roel C H Vermeulen
  79. Department of Epidemiology, German Institute for Human Nutrition, Potsdam, Germany.

    • Heiner Boeing
  80. Danish Cancer Society Research Center, Copenhagen, Denmark.

    • Anne Tjonneland
  81. Hematology Unit, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari, Italy.

    • Emanuele Angelucci
  82. Department of Surgery and Translational Medicine, Section of Anatomo-Pathology, University of Florence, Florence, Italy.

    • Simonetta Di Lollo
  83. Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, Italy.

    • Marco Rais
  84. Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Francine Laden
  85. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Edward Giovannucci
  86. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft
    •  & Liming Liang
  87. College of Information Science and Technology, Dalian Maritime University, Dalian, China.

    • Baoshan Ma
  88. Department of Health Studies, University of Chicago, Chicago, Illinois, USA.

    • Brian C H Chiu
  89. Dongguk University–Seoul, Seoul, South Korea.

    • Ju-Hyun Park
  90. Department of Pathology, City of Hope National Medical Center, Duarte, California, USA.

    • Dennis D Weisenburger
  91. Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

    • Karin E Smedby
  92. Department of Hematology, Hospices Civils de Lyon, Pierre-Benite, France.

    • Gilles Salles
  93. Department of Hematology, Université Lyon 1, Pierre-Benite, France.

    • Gilles Salles

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Contributions

J.R.C., S.I.B., S.S.W., A.N., A.R.B.-W., Q.L., G. Severi, M. Melbye, L.R.T., M.P.P., C.L., B.M.B., S.L.S., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. organized and designed the study. J.R.C., L.C., L.B., A.H., P.M.B., E.A.H., S.L.S., G. Salles, C.F.S., N.R. and S.J.C. conducted and supervised the genotyping of samples. J.R.C., S.I.B., J. Vijai, Z.W., M.Y., L.C., P.I.W.d.B., D.C., J.G., D. Zhi, Y.W.A., J.H., B.M., J.S., L.L., J.-H.P., C.C.C., N.C., S.d.S., K.E.S., C.F.S., N.R. and S.J.C. contributed to the design and execution of statistical analysis. J.R.C., S.I.B., J. Vijai, H.G., J.M., S.S.W., Z.W., M.Y., L.C., A.N., D.C., A.M., C.R.F., A.J.D.R., C.L., K.E.S., C.F.S., N.R. and S.J.C. wrote the first draft of the manuscript. J.R.C., J. Vijai, H.G., J.M., S.S.W., L.C., A.N., L.B., A.M., A.R.B.-W., Q.L., G. Severi, M. Melbye, J.G., R.D.J., E.K., L.R.T., M.P.P., C.M.V., J.J.S., G.G.G., D.A., R.S.K., M.Z., K.A.B., A.Z.-J., T.M.H., B.K.L., A.J.N., A.D., Y.W.A., M.L., C.A.T., S.M.A., T.E.W., G.J.W., A.S.V., D. Zelenika, H.T., C.H., T.J.M., H.H., B.G., H.-O.A., P.M.B., J.R., M.T.S., E.A.H., W.C., P.H., L.M.M., R.K.S., L.F.T., K.E.N., N.B., Y.B., P. Boffetta, P. Brennan, L.F., M. Maynadie, A. Staines, T.L., S.C., A. Smith, E. Roman, W.R.D., K.O., A.Z., R.J.K., D.J.V., T.Z., Y.Z., T.R.H., A.K., J.T., M.C.S., J.C., J. Virtamo, S.W., E. Riboli, P.V., R.K., D.T., R.C.H.V., H.B., A.T., E.A., S.D.L., M.R., B.M.B., F.L., E.G., P.K., Y.Y., B.C.H.C., D.D.W., N.C., J.F.F., S.L.S., X.W., S.d.S., K.E.S., G. Salles, C.F.S. and N.R. conducted the epidemiological studies and contributed samples to the GWAS and/or follow-up genotyping. All authors contributed to the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to James R Cerhan.

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    Supplementary Figures 1–7, Supplementary Tables 1–5, 7–11 and 13, and Supplementary Note.

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DOI

https://doi.org/10.1038/ng.3105

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