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Nat Commun. 2018 Feb 8;9(1):556. doi: 10.1038/s41467-018-02942-5.

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.

Klein AP1,2, Wolpin BM3, Risch HA4, Stolzenberg-Solomon RZ5, Mocci E6, Zhang M7, Canzian F8, Childs EJ6, Hoskins JW7, Jermusyk A7, Zhong J7, Chen F6, Albanes D5, Andreotti G5, Arslan AA9,10,11, Babic A3, Bamlet WR12, Beane-Freeman L5, Berndt SI5, Blackford A6, Borges M13, Borgida A14, Bracci PM15, Brais L3, Brennan P16, Brenner H17,18,19, Bueno-de-Mesquita B20,21,22,23, Buring J24,25, Campa D26, Capurso G27, Cavestro GM28, Chaffee KG12, Chung CC5,29, Cleary S14, Cotterchio M30,31, Dijk F32, Duell EJ33, Foretova L34, Fuchs C35, Funel N36, Gallinger S14, M Gaziano JM37,38, Gazouli M39, Giles GG40,41,42, Giovannucci E3, Goggins M13, Goodman GE43, Goodman PJ44, Hackert T45, Haiman C46, Hartge P5, Hasan M47, Hegyi P48, Helzlsouer KJ49, Herman J50, Holcatova I51, Holly EA15, Hoover R5, Hung RJ14, Jacobs EJ52, Jamroziak K53, Janout V54,55, Kaaks R56, Khaw KT57, Klein EA58, Kogevinas M59,60,61,62, Kooperberg C43, Kulke MH3, Kupcinskas J63, Kurtz RJ64, Laheru D6, Landi S26, Lawlor RT65, Lee IM24,66, LeMarchand L67, Lu L4, Malats N68,69, Mambrini A70, Mannisto S71, Milne RL40,41, Mohelníková-Duchoňová B72, Neale RE73, Neoptolemos JP74, Oberg AL12, Olson SH75, Orlow I75, Pasquali C76, Patel AV52, Peters U43, Pezzilli R77, Porta M60,61, Real FX69,78,79, Rothman N5, Scelo G16, Sesso HD24,25, Severi G40,41,80, Shu XO81, Silverman D5, Smith JP82, Soucek P83, Sund M84, Talar-Wojnarowska R85, Tavano F86, Thornquist MD43, Tobias GS5, Van Den Eeden SK87, Vashist Y88, Visvanathan K89, Vodicka P90, Wactawski-Wende J91, Wang Z92, Wentzensen N5, White E43,93, Yu H67, Yu K5, Zeleniuch-Jacquotte A10,94, Zheng W81, Kraft P25,95, Li D96, Chanock S5, Obazee O8, Petersen GM12, Amundadottir LT97.

Author information

1
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. aklein1@jhmi.edu.
2
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. aklein1@jhmi.edu.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
4
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA.
5
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
6
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA.
7
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
8
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
9
Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, 10016, USA.
10
Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA.
11
Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA.
12
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
13
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.
14
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1×5, Canada.
15
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA.
16
International Agency for Research on Cancer (IARC), 69372, Lyon, France.
17
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
18
Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
19
National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
20
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands.
21
Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX, Utrecht, The Netherlands.
22
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, SW7 2AZ, UK.
23
Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
24
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
25
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
26
Department of Biology, University of Pisa, 56126, Pisa, Italy.
27
Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy.
28
Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
29
Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
30
Cancer Care Ontario, University of Toronto, Toronto, Ontario, M5G 2L7, Canada.
31
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada.
32
Department of Pathology, Academic Medical Center, University of Amsterdam, 1007 MB, Amsterdam, The Netherlands.
33
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain.
34
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653, Brno, Czech Republic.
35
Yale Cancer Center, New Haven, CT, 06510, USA.
36
Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy.
37
Division of Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA.
38
Boston VA Healthcare System, Boston, MA, 02132, USA.
39
Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 106 79, Athens, Greece.
40
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
41
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia.
42
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia.
43
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
44
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
45
Department of General Surgery, University Hospital Heidelberg, 69120, Heidelberg, Germany.
46
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA.
47
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA.
48
First Department of Medicine, University of Szeged, 6725, Szeged, Hungary.
49
Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
50
Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA.
51
Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, 150 06, Prague 5, Czech Republic.
52
Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA.
53
Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776, Warsaw, Poland.
54
Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, 701 03, Ostrava, Czech Republic.
55
Faculty of Medicine, University of Olomouc, 771 47, Olomouc, Czech Republic.
56
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
57
School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK.
58
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
59
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain.
60
CIBER Epidemiología y Salud Pública (CIBERESP), 08003, Barcelona, Spain.
61
Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, 08003, Barcelona, Spain.
62
Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain.
63
Department of Gastroenterology, Lithuanian University of Health Sciences, 44307, Kaunas, Lithuania.
64
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
65
ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134, Verona, Italy.
66
Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA.
67
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
68
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain.
69
CIBERONC, 28029, Madrid, Spain.
70
Oncology Department, ASL1 Massa Carrara, Carrara, 54033, Italy.
71
Department of Public Health Solutions, National Institute for Health and Welfare, 00271, Helsinki, Finland.
72
Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, 775 20, Olomouc, Czech Republic.
73
Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia.
74
Department of General Surgery, University of Heidelburg, Heidelberg, Germany.
75
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
76
Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35124, Padua, Italy.
77
Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, 40138, Bologna, Italy.
78
Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain.
79
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002, Barcelona, Spain.
80
Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, 94800, Villejuif, France.
81
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
82
Department of Medicine, Georgetown University, Washington, 20057, USA.
83
Laboratory for Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00, Pilsen, Czech Republic.
84
Department of Surgical and Perioperative Sciences, Umeå University, 901 85, Umeå, Sweden.
85
Department of Digestive Tract Diseases, Medical University of Łodz, 90-647, Łodz, Poland.
86
Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy.
87
Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA.
88
Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, 20246, Hamburg, Germany.
89
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
90
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic.
91
Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, 14214, USA.
92
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
93
Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA.
94
Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.
95
Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA.
96
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
97
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. amundadottirl@mail.nih.gov.

Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

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