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

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

Cerhan JR1, Berndt SI2, Vijai J3, Ghesquières H4, McKay J5, Wang SS6, Wang Z7, Yeager M7, Conde L8, de Bakker PI9, Nieters A10, Cox D11, Burdett L7, Monnereau A12, Flowers CR13, De Roos AJ14, Brooks-Wilson AR15, Lan Q2, Severi G16, Melbye M17, Gu J18, Jackson RD19, Kane E20, Teras LR21, Purdue MP2, Vajdic CM22, Spinelli JJ23, Giles GG24, Albanes D2, Kelly RS25, Zucca M26, Bertrand KA27, Zeleniuch-Jacquotte A28, Lawrence C29, Hutchinson A7, Zhi D30, Habermann TM31, Link BK32, Novak AJ31, Dogan A33, Asmann YW34, Liebow M31, Thompson CA31, Ansell SM31, Witzig TE31, Weiner GJ32, Veron AS11, Zelenika D35, Tilly H36, Haioun C37, Molina TJ38, Hjalgrim H39, Glimelius B40, Adami HO41, Bracci PM42, Riby J8, Smith MT43, Holly EA42, Cozen W44, Hartge P2, Morton LM2, Severson RK45, Tinker LF46, North KE47, Becker N48, Benavente Y49, Boffetta P50, Brennan P51, Foretova L52, Maynadie M53, Staines A54, Lightfoot T20, Crouch S20, Smith A20, Roman E20, Diver WR21, Offit K3, Zelenetz A3, Klein RJ3, Villano DJ3, Zheng T55, Zhang Y55, Holford TR56, Kricker A57, Turner J58, Southey MC59, Clavel J60, Virtamo J61, Weinstein S2, Riboli E62, Vineis P63, Kaaks R48, Trichopoulos D64, Vermeulen RC65, Boeing H66, Tjonneland A67, Angelucci E68, Di Lollo S69, Rais M70, Birmann BM71, Laden F72, Giovannucci E73, Kraft P74, Huang J75, Ma B76, Ye Y18, Chiu BC77, Sampson J2, Liang L74, Park JH78, Chung CC2, Weisenburger DD79, Chatterjee N2, Fraumeni JF Jr2, Slager SL1, Wu X18, de Sanjose S49, Smedby KE80, Salles G81, Skibola CF8, Rothman N2, Chanock SJ2.

Author information

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.

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.

PMID:
25261932
PMCID:
PMC4213349
DOI:
10.1038/ng.3105
[Indexed for MEDLINE]
Free PMC Article
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