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Nat Genet. 2014 Sep;46(9):994-1000. doi: 10.1038/ng.3052. Epub 2014 Aug 3.

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.

Wolpin BM1, Rizzato C2, Kraft P3, Kooperberg C4, Petersen GM5, Wang Z6, Arslan AA7, Beane-Freeman L8, Bracci PM9, Buring J10, Canzian F11, Duell EJ12, Gallinger S13, Giles GG14, Goodman GE15, Goodman PJ16, Jacobs EJ17, Kamineni A18, Klein AP19, Kolonel LN20, Kulke MH21, Li D22, Malats N23, Olson SH24, Risch HA25, Sesso HD26, Visvanathan K27, White E28, Zheng W29, Abnet CC8, Albanes D8, Andreotti G8, Austin MA30, Barfield R31, Basso D32, Berndt SI8, Boutron-Ruault MC33, Brotzman M34, Büchler MW35, Bueno-de-Mesquita HB36, Bugert P37, Burdette L6, Campa D38, Caporaso NE8, Capurso G39, Chung C6, Cotterchio M40, Costello E41, Elena J42, Funel N43, Gaziano JM44, Giese NA35, Giovannucci EL45, Goggins M46, Gorman MJ21, Gross M47, Haiman CA48, Hassan M22, Helzlsouer KJ49, Henderson BE50, Holly EA9, Hu N8, Hunter DJ51, Innocenti F52, Jenab M53, Kaaks R38, Key TJ54, Khaw KT55, Klein EA56, Kogevinas M57, Krogh V58, Kupcinskas J59, Kurtz RC60, LaCroix A15, Landi MT8, Landi S61, Le Marchand L62, Mambrini A63, Mannisto S64, Milne RL65, Nakamura Y66, Oberg AL67, Owzar K68, Patel AV17, Peeters PH69, Peters U70, Pezzilli R71, Piepoli A72, Porta M73, Real FX74, Riboli E75, Rothman N8, Scarpa A76, Shu XO29, Silverman DT8, Soucek P77, Sund M78, Talar-Wojnarowska R79, Taylor PR8, Theodoropoulos GE80, Thornquist M15, Tjønneland A81, Tobias GS8, Trichopoulos D82, Vodicka P83, Wactawski-Wende J84, Wentzensen N8, Wu C85, Yu H62, Yu K8, Zeleniuch-Jacquotte A86, Hoover R8, Hartge P87, Fuchs C88, Chanock SJ89, Stolzenberg-Solomon RS87, Amundadottir LT87.

Author information

1
1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3].
2
1] Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2].
3
1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. [3].
4
1] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2].
5
1] Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. [2].
6
1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
7
1] Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA. [2] Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. [3] New York University Cancer Institute, New York, New York, USA.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
9
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
10
1] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
11
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
12
Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
13
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
14
1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. [3] Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
15
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
16
Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
17
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
18
Group Health Research Institute, Seattle, Washington, USA.
19
1] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland, USA.
20
The Cancer Research Center of Hawaii (retired), Honolulu, Hawaii, USA.
21
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
22
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
23
Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain.
24
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
25
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
26
1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
27
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
28
1] Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington, USA.
29
1] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
30
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
31
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
32
Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy.
33
1] INSERM, Centre for Research in Epidemiology and Population Health (CESP), Nutrition, Hormones and Women's Health Team, Villejuif, France. [2] University Paris Sud, UMRS 1018, Villejuif, France. [3] Institut Gustave Roussy (IGR), Villejuif, France.
34
Westat, Rockville, Maryland, USA.
35
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
36
1] National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. [2] Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands. [3] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
37
Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim, Germany.
38
Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
39
Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy.
40
1] Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
41
National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK.
42
Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
43
Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
44
1] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Massachusetts Veteran's Epidemiology, Research and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA.
45
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.
46
1] Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. [3] Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.
47
Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.
48
Preventive Medicine, University of Southern California, Los Angeles, California, USA.
49
Prevention and Research Center, Mercy Medical Center, Baltimore, Maryland, USA.
50
Cancer Prevention, University of Southern California, Los Angeles, California, USA.
51
1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard School of Public Health, Boston, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA.
52
The University of North Carolina Eshelman School of Pharmacy, Center for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, North Carolina, USA.
53
International Agency for Research on Cancer, Lyon, France.
54
Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
55
School of Clinical Medicine, University of Cambridge, Cambridge, UK.
56
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.
57
1] Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. [2] Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. [3] Department of Nutrition, National School of Public Health, Athens, Greece.
58
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
59
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
60
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
61
Department of Biology, University of Pisa, Pisa, Italy.
62
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
63
Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
64
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
65
1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
66
Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
67
Alliance Statistics and Data Center, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
68
Alliance Statistics and Data Center, Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.
69
1] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
70
Department of Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
71
Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
72
Department of Gastroenterology, Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, Italy.
73
1] Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. [2] Department of Epidemiology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. [3] CIBERESP, Madrid, Spain.
74
1] Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. [2] Departament de Ciències i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
75
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
76
ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
77
Toxicogenomics Unit, Center for Toxicology and Safety, National Institute of Public Health, Prague, Czech Republic.
78
Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden.
79
Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
80
1st Propaideutic Surgical Department, Hippocration University Hospital, Athens, Greece.
81
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
82
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.
83
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
84
Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA.
85
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
86
1] Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. [2] New York University Cancer Institute, New York, New York, USA.
87
1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2].
88
1] Department of Medical Oncology, Dana-Farber Cancer Institute, 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].
89
1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [3].

Abstract

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

PMID:
25086665
PMCID:
PMC4191666
DOI:
10.1038/ng.3052
[Indexed for MEDLINE]
Free PMC Article

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