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Nat Commun. 2016 Mar 9;7:10933. doi: 10.1038/ncomms10933.

Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

Berndt SI1, Camp NJ2, Skibola CF3,4, Vijai J5, Wang Z6, Gu J7, Nieters A8, Kelly RS9,10, Smedby KE11, Monnereau A12,13,14, Cozen W15,16, Cox A17, Wang SS18, Lan Q1, Teras LR19, Machado M1,20, Yeager M6, Brooks-Wilson AR21,22, Hartge P1, Purdue MP23, Birmann BM24, Vajdic CM25, Cocco P26, Zhang Y27, Giles GG28,29, Zeleniuch-Jacquotte A30,31,32, Lawrence C33, Montalvan R33, Burdett L6, Hutchinson A6, Ye Y7, Call TG34, Shanafelt TD35, Novak AJ35, Kay NE34, Liebow M35, Cunningham JM36, Allmer C37, Hjalgrim H38, Adami HO9,39, Melbye M38,40, Glimelius B41, Chang ET42,43, Glenn M44, Curtin K45, Cannon-Albright LA45,46, Diver WR19, Link BK47, Weiner GJ47, Conde L3,4, Bracci PM48, Riby J3,4, Arnett DK3, Zhi D49, Leach JM49, Holly EA48, Jackson RD50, Tinker LF51, Benavente Y52,53, Sala N54,55, Casabonne D56,57, Becker N58, Boffetta P59, Brennan P60, Foretova L61, Maynadie M62, McKay J60, Staines A63, Chaffee KG37, Achenbach SJ37, Vachon CM37, Goldin LR1, Strom SS7, Leis JF64, Weinberg JB65, Caporaso NE1, Norman AD37, De Roos AJ51,66, Morton LM1, Severson RK67, Riboli E68, Vineis P10,69, Kaaks R58, Masala G70, Weiderpass E39,71,72,73, Chirlaque MD53,74, Vermeulen RC75,76, Travis RC77, Southey MC78, Milne RL28,29, Albanes D1, Virtamo J79, Weinstein S1, Clavel J12,13, Zheng T27, Holford TR80, Villano DJ5, Maria A5, Spinelli JJ81,82, Gascoyne RD83,84, Connors JM83,85, Bertrand KA9,24, Giovannucci E9,24,86, Kraft P9,87, Kricker A88, Turner J89,90, Ennas MG91, Ferri GM92, Miligi L93, Liang L9,87, Ma B9,94, Huang J9, Crouch S95, Park JH96, Chatterjee N1, North KE97,98, Snowden JA17,99, Wright J17,99, Fraumeni JF1, Offit K5, Wu X7, de Sanjose S52,53, Cerhan JR37, Chanock SJ1, Rothman N1, Slager SL37.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
2
Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute and University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
3
Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
4
Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, California 94720, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
6
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, Maryland 20877, USA.
7
Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
8
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, 79108 Baden-Württemberg, Germany.
9
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
10
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
11
Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm 17176, Sweden.
12
Epidemiology of Childhood and Adolescent Cancers Group, INSERM, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), F-94807 Paris, France.
13
Université Paris Descartes, 75270 Paris, France.
14
Registre des hémopathies malignes de la Gironde, Institut Bergonié, 33076 Bordeaux Cedex, France.
15
Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
16
Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
17
Department of Oncology, University of Sheffield, Sheffield, South Yorkshire S10 1NS, UK.
18
Division of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, California 91030, USA.
19
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
20
Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
21
Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.
22
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada V5A1S6.
23
Ontario Health Study, Toronto, Ontario, Canada M5G 0A3.
24
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
25
Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
26
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, 09042 Cagliari, Italy.
27
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06520, USA.
28
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
29
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
30
Department of Population Health, New York University School of Medicine, New York, New York 10016, USA.
31
Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016, USA.
32
Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York 10016, USA.
33
Westat, Rockville, Maryland 20850, USA.
34
Division of Hematology, Mayo Clinic, Rochester, Minnesota 55905, USA.
35
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
36
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
37
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
38
Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, 2300 Copenhagen, Denmark.
39
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.
40
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
41
Department of Immunology, Genetics and Pathology, Uppsala University, 75105 Uppsala, Sweden.
42
Center for Epidemiology and Computational Biology, Health Sciences, Exponent, Inc., Menlo Park, California 94025, USA.
43
Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California 94305, USA.
44
Department of Internal Medicine, Huntsman Cancer Institute, Salt Lake City, Utah 84112, USA.
45
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.
46
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah 84148, USA.
47
Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
48
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94118, USA.
49
Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
50
Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA.
51
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98117, USA.
52
Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona 08908, Spain.
53
CIBER de Epidemiología y Salud Pública (CIBERESP), 08036 Barcelona, Spain.
54
Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
55
Translational Research Laboratory, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
56
Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Catala d'Oncologia, IDIBELL, 08908L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
57
CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.
58
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120 Baden-Württemberg, Germany.
59
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
60
International Agency for Research on Cancer (IARC), 69372 Lyon, France.
61
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, 656 53 Brno, Czech Republic.
62
EA 4184, Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, 21070 Dijon, France.
63
School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland.
64
Division of Hematology/Oncology, Mayo Clinic, Phoenix, Arizona 85054, USA.
65
Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina 27710, USA.
66
Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, Pennsylvania 19104, USA.
67
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
68
School of Public Health, Imperial College London, London W2 1PG, UK.
69
Human Genetics Foundation, 10126 Turin, Italy.
70
Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), 50139 Florence, Italy.
71
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, N-9037 Tromsø, Norway.
72
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, N-0304 Oslo, Norway.
73
Genetic Epidemiology Group, Folkhälsan Research Center, FI-00250 Helsinki, Finland.
74
Department of Epidemiology, Murcia Regional Health Authority, E30008 Murcia, Spain.
75
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, 3508, TD, The Netherlands.
76
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
77
Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK.
78
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
79
Chronic Disease Prevention Unit, National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
80
Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut 06520, USA.
81
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.
82
School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.
83
Center for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.
84
Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.
85
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.
86
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
87
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
88
Sydney School of Public Health, The University of Sydney, Sydney, New South Wales 2006, Australia.
89
Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
90
Department of Histopathology, Douglass Hanly Moir Pathology, Sydney, New South Wales 2113, Australia.
91
Department of Biomedical Science, University of Cagliari, Monserrato, 09042 Cagliari, Italy.
92
Interdisciplinary Department of Medicine, University of Bari, 70124 Bari, Italy.
93
Environmental and Occupational Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), 50139 Florence, Italy.
94
College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning Province 116026, China.
95
Department of Health Sciences, University of York, York YO10 5DD, UK.
96
Department of Statistics, Dongguk University, Seoul 100-715, Republic of Korea.
97
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
98
Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
99
Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, South Yorkshire S10 2TN, UK.

Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

PMID:
26956414
PMCID:
PMC4786871
DOI:
10.1038/ncomms10933
[Indexed for MEDLINE]
Free PMC Article

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