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

James R Cerhan; Sonja I Berndt; Joseph Vijai; Hervé Ghesquières; James McKay; Sophia S Wang; Zhaoming Wang; Meredith Yeager; Lucia Conde; Paul I W de Bakker; Alexandra Nieters; David Cox; Laurie Burdett; Alain Monnereau; Christopher R Flowers; Anneclaire J De Roos; Angela R Brooks-Wilson; Qing Lan; Gianluca Severi; Mads Melbye; Jian Gu; Rebecca D Jackson; Eleanor Kane; Lauren R Teras; Mark P Purdue; Claire M Vajdic; John J Spinelli; Graham G Giles; Demetrius Albanes; Rachel S Kelly; Mariagrazia Zucca; Kimberly A Bertrand; Anne Zeleniuch-Jacquotte; Charles Lawrence; Amy Hutchinson; Degui Zhi; Thomas M Habermann; Brian K Link; Anne J Novak; Ahmet Dogan; Yan W Asmann; Mark Liebow; Carrie A Thompson; Stephen M Ansell; Thomas E Witzig; George J Weiner; Amelie S Veron; Diana Zelenika; Hervé Tilly; Corinne Haioun; Thierry Jo Molina; Henrik Hjalgrim; Bengt Glimelius; Hans-Olov Adami; Paige M Bracci; Jacques Riby; Martyn T Smith; Elizabeth A Holly; Wendy Cozen; Patricia Hartge; Lindsay M Morton; Richard K Severson; Lesley F Tinker; Kari E North; Nikolaus Becker; Yolanda Benavente; Paolo Boffetta; Paul Brennan; Lenka Foretova; Marc Maynadie; Anthony Staines; Tracy Lightfoot; Simon Crouch; Alex Smith; Eve Roman; W Ryan Diver; Kenneth Offit; Andrew Zelenetz; Robert J Klein; Danylo J Villano; Tongzhang Zheng; Yawei Zhang; Theodore R Holford; Anne Kricker; Jenny Turner; Melissa C Southey; Jacqueline Clavel; Jarmo Virtamo; Stephanie Weinstein; Elio Riboli; Paolo Vineis; Rudolph Kaaks; Dimitrios Trichopoulos; Roel C H Vermeulen; Heiner Boeing; Anne Tjonneland; Emanuele Angelucci; Simonetta Di Lollo; Marco Rais; Brenda M Birmann; Francine Laden; Edward Giovannucci; Peter Kraft; Jinyan Huang; Baoshan Ma; Yuanqing Ye; Brian C H Chiu; Joshua Sampson; Liming Liang; Ju-Hyun Park; Charles C Chung; Dennis D Weisenburger; Nilanjan Chatterjee; Joseph F Fraumeni Jr; Susan L Slager; Xifeng Wu; Silvia de Sanjose; Karin E Smedby; Gilles Salles; Christine F Skibola; Nathaniel Rothman; Stephen J Chanock

doi:10.1038/ng.3105

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

Nat Genet. 2014 Nov;46(11):1233-8. doi: 10.1038/ng.3105. Epub 2014 Sep 28.

Authors

James R Cerhan¹, Sonja I Berndt², Joseph Vijai³, Hervé Ghesquières⁴, James McKay⁵, Sophia S Wang⁶, Zhaoming Wang⁷, Meredith Yeager⁷, Lucia Conde⁸, Paul I W de Bakker⁹, Alexandra Nieters¹⁰, David Cox¹¹, Laurie Burdett⁷, Alain Monnereau¹², Christopher R Flowers¹³, Anneclaire J De Roos¹⁴, Angela R Brooks-Wilson¹⁵, Qing Lan², Gianluca Severi¹⁶, Mads Melbye¹⁷, Jian Gu¹⁸, Rebecca D Jackson¹⁹, Eleanor Kane²⁰, Lauren R Teras²¹, Mark P Purdue², Claire M Vajdic²², John J Spinelli²³, Graham G Giles²⁴, Demetrius Albanes², Rachel S Kelly²⁵, Mariagrazia Zucca²⁶, Kimberly A Bertrand²⁷, Anne Zeleniuch-Jacquotte²⁸, Charles Lawrence²⁹, Amy Hutchinson⁷, Degui Zhi³⁰, Thomas M Habermann³¹, Brian K Link³², Anne J Novak³¹, Ahmet Dogan³³, Yan W Asmann³⁴, Mark Liebow³¹, Carrie A Thompson³¹, Stephen M Ansell³¹, Thomas E Witzig³¹, George J Weiner³², Amelie S Veron¹¹, Diana Zelenika³⁵, Hervé Tilly³⁶, Corinne Haioun³⁷, Thierry Jo Molina³⁸, Henrik Hjalgrim³⁹, Bengt Glimelius⁴⁰, Hans-Olov Adami⁴¹, Paige M Bracci⁴², Jacques Riby⁸, Martyn T Smith⁴³, Elizabeth A Holly⁴², Wendy Cozen⁴⁴, Patricia Hartge², Lindsay M Morton², Richard K Severson⁴⁵, Lesley F Tinker⁴⁶, Kari E North⁴⁷, Nikolaus Becker⁴⁸, Yolanda Benavente⁴⁹, Paolo Boffetta⁵⁰, Paul Brennan⁵¹, Lenka Foretova⁵², Marc Maynadie⁵³, Anthony Staines⁵⁴, Tracy Lightfoot²⁰, Simon Crouch²⁰, Alex Smith²⁰, Eve Roman²⁰, W Ryan Diver²¹, Kenneth Offit³, Andrew Zelenetz³, Robert J Klein³, Danylo J Villano³, Tongzhang Zheng⁵⁵, Yawei Zhang⁵⁵, Theodore R Holford⁵⁶, Anne Kricker⁵⁷, Jenny Turner⁵⁸, Melissa C Southey⁵⁹, Jacqueline Clavel⁶⁰, Jarmo Virtamo⁶¹, Stephanie Weinstein², Elio Riboli⁶², Paolo Vineis⁶³, Rudolph Kaaks⁴⁸, Dimitrios Trichopoulos⁶⁴, Roel C H Vermeulen⁶⁵, Heiner Boeing⁶⁶, Anne Tjonneland⁶⁷, Emanuele Angelucci⁶⁸, Simonetta Di Lollo⁶⁹, Marco Rais⁷⁰, Brenda M Birmann⁷¹, Francine Laden⁷², Edward Giovannucci⁷³, Peter Kraft⁷⁴, Jinyan Huang⁷⁵, Baoshan Ma⁷⁶, Yuanqing Ye¹⁸, Brian C H Chiu⁷⁷, Joshua Sampson², Liming Liang⁷⁴, Ju-Hyun Park⁷⁸, Charles C Chung², Dennis D Weisenburger⁷⁹, Nilanjan Chatterjee², Joseph F Fraumeni Jr², Susan L Slager¹, Xifeng Wu¹⁸, Silvia de Sanjose⁴⁹, Karin E Smedby⁸⁰, Gilles Salles⁸¹, Christine F Skibola⁸, Nathaniel Rothman², Stephen J Chanock²

Affiliations

¹ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
³ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
⁴ 1] Department of Hematology, Centre Léon Bérard, Lyon, France. [2] Laboratoire de Biologie Moléculaire de la Cellule, UMR 5239, CNRS, Pierre-Benite, France.
⁵ Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer, Lyon, France.
⁶ Department of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, California, USA.
⁷ Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland, USA.
⁸ 1] Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, Alabama, USA. [2] Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, California, USA.
⁹ 1] Department of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁰ Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
¹¹ Lyon, France.
¹² 1] Environmental Epidemiology of Cancer Group, INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France. [2] UMRS 1018, Université Paris Sud, Villejuif, France. [3] Registre des Hémopathies Malignes de la Gironde, Institut Bergonié, Bordeaux, France.
¹³ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁴ 1] Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, Pennsylvania, USA. [2] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁵ 1] Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
¹⁶ 1] Human Genetics Foundation, Turin, Italy. [2] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [3] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Victoria, Australia.
¹⁷ 1] Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark. [2] Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹⁸ Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA.
¹⁹ Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio, USA.
²⁰ Department of Health Sciences, University of York, York, UK.
²¹ Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
²² Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
²³ 1] Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.
²⁴ 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, Victoria, Australia.
²⁵ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Medical Research Council (MRC)-Public Health England (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
²⁶ Department of Biomedical Science, University of Cagliari, Monserrato, Italy.
²⁷ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
²⁸ 1] Department of Population Health, New York University School of Medicine, New York, New York, USA. [2] Cancer Institute, New York University School of Medicine, New York, New York, USA.
²⁹ Health Studies Sector, Westat, Rockville, Maryland, USA.
³⁰ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
³¹ Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
³² Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA.
³³ Department of Laboratory Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
³⁴ Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA.
³⁵ Centre National de Génotypage, Evry, France.
³⁶ Centre Heni Becquerel, Rouen, France.
³⁷ Department of Hematology, Centre Hospitalier Universitaire (CHU) Henri Mondor, Creteil, France.
³⁸ Department of Pathology, Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
³⁹ Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.
⁴⁰ 1] Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. [2] Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden.
⁴¹ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴² Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
⁴³ Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, California, USA.
⁴⁴ 1] Department of Preventive Medicine, University of Southern California Keck School of Medicine, University of Southern California, Los Angeles, California, USA. [2] Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁴⁵ Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, USA.
⁴⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁴⁷ 1] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁹ 1] Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Catala d'Oncologia, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. [2] Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
⁵⁰ Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵¹ Group of Genetic Epidemiology, Section of Genetics, International Agency for Research on Cancer, Lyon, France.
⁵² Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Masaryk University, Brno, Czech Republic.
⁵³ Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon, France.
⁵⁴ School of Nursing and Human Sciences, Dublin City University, Dublin, Ireland.
⁵⁵ Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA.
⁵⁶ Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.
⁵⁷ Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.
⁵⁸ 1] Pathology, Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia. [2] Department of Histopathology, Douglass Hanly Moir Pathology, Macquarie Park, New South Wales, Australia.
⁵⁹ Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
⁶⁰ 1] Environmental Epidemiology of Cancer Group, INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France. [2] UMRS 1018, Université Paris Sud, Villejuif, France.
⁶¹ Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
⁶² School of Public Health, Imperial College London, London, UK.
⁶³ 1] Human Genetics Foundation, Turin, Italy. [2] Medical Research Council (MRC)-Public Health England (PHE) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁶⁴ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [3] Hellenic Health Foundation, Athens, Greece.
⁶⁵ 1] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
⁶⁶ Department of Epidemiology, German Institute for Human Nutrition, Potsdam, Germany.
⁶⁷ Danish Cancer Society Research Center, Copenhagen, Denmark.
⁶⁸ Hematology Unit, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari, Italy.
⁶⁹ Department of Surgery and Translational Medicine, Section of Anatomo-Pathology, University of Florence, Florence, Italy.
⁷⁰ Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, Italy.
⁷¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁷² 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
⁷³ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
⁷⁴ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
⁷⁵ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
⁷⁶ 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] College of Information Science and Technology, Dalian Maritime University, Dalian, China.
⁷⁷ Department of Health Studies, University of Chicago, Chicago, Illinois, USA.
⁷⁸ Dongguk University-Seoul, Seoul, South Korea.
⁷⁹ Department of Pathology, City of Hope National Medical Center, Duarte, California, USA.
⁸⁰ Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
⁸¹ 1] Laboratoire de Biologie Moléculaire de la Cellule, UMR 5239, CNRS, Pierre-Benite, France. [2] Department of Hematology, Hospices Civils de Lyon, Pierre-Benite, France. [3] Department of Hematology, Université Lyon 1, Pierre-Benite, France.

PMID: 25261932
PMCID: PMC4213349
DOI: 10.1038/ng.3105

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Intramural

MeSH terms

Chromosome Mapping
Computational Biology
Genetic Loci / genetics*
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Genotype
Humans
Likelihood Functions
Lymphoma, Large B-Cell, Diffuse / genetics*
Polymorphism, Single Nucleotide / genetics
Quantitative Trait Loci / genetics
White People / genetics*

Abstract

Publication types

MeSH terms

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