A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

Gloria M. Petersen, Laufey Amundadottir, Charles S. Fuchs, Peter Kraft, Rachael Z. Stolzenberg-Solomon, Kevin B. Jacobs, Alan A. Arslan, H. Bas Bueno-De-Mesquita, Steven Gallinger, Myron Gross, Kathy Helzlsouer, Elizabeth A. Holly, Eric J. Jacobs, Alison P. Klein, Andrea Lacroix, Donghui Li, Margaret T. Mandelson, Sara H. Olson, Harvey A. Risch, Wei ZhengDemetrius Albanes, William R. Bamlet, Christine D. Berg, Marie Christine Boutron-Ruault, Julie E. Buring, Paige M. Bracci, Federico Canzian, Sandra Clipp, Michelle Cotterchio, Mariza De Andrade, Eric J. Duell, J. Michael Gaziano, Edward L. Giovannucci, Michael Goggins, Göran Hallmans, Susan E. Hankinson, Manal Hassan, Barbara Howard, David J. Hunter, Amy Hutchinson, Mazda Jenab, Rudolf Kaaks, Charles Kooperberg, Vittorio Krogh, Robert C. Kurtz, Shannon M. Lynch, Robert R. McWilliams, Julie B. Mendelsohn, Dominique S. Michaud, Hemang Parikh, Alpa V. Patel, Petra H M Peeters, Aleksandar Rajkovic, Elio Riboli, Laudina Rodriguez, Daniela Seminara, Xiao Ou Shu, Gilles Thomas, Anne Tjønneland, Geoffrey S. Tobias, Dimitrios Trichopoulos, Stephen K. Van Den Eeden, Jarmo Virtamo, Jean Wactawski-Wende, Zhaoming Wang, Brian M. Wolpin, Herbert Yu, Kai Yu, Anne Zeleniuch-Jacquotte, Joseph F. Fraumeni, Robert N. Hoover, Patricia Hartge, Stephen J. Chanock

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418 Scopus citations

Abstract

We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 × 10 11, per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 × 10 8, per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 × 10 10, per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 × 10 7, per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.

Original languageEnglish (US)
Pages (from-to)224-228
Number of pages5
JournalNature Genetics
Volume42
Issue number3
DOIs
StatePublished - Mar 2010

Bibliographical note

Funding Information:
1Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA. 2Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, Maryland, USA. 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 5Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 6Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. 7Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. 8Core Genotyping Facility, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA. 9Bioinformed Consulting Services, Gaithersburg, Maryland, USA. 10Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA. 11Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. 12New York University Cancer Institute, New York, New York, USA. 13National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands and Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands. 14Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 15Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. 16Prevention and Research Center, Mercy Medical Center, Baltimore, Maryland, USA. 17Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA. 18Department of Epidemiology, American Cancer Society, Atlanta, Georgia, USA. 19Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 20Department of Epidemiology, Bloomberg School of Public Health, The Sol Goldman Pancreatic Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. 21Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 22Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. 23Group Health Center for Health Studies, Seattle, Washington, USA. 24Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. 25Yale University School of Public Health, New Haven, Connecticut, USA. 26Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA. 27Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 28Inserm, Paris-Sud University, Institut Gustave-Roussy, Villejuif, France. 29Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. 30Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts, USA. 31German Cancer Research Center (DKFZ), Heidelberg, Germany. 32Johns Hopkins Bloomberg School of Public Health, George W. Comstock Center for Public Health Research and Prevention, Hagerstown, Maryland, USA. 33Cancer Care Ontario and Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 34Catalan Institute of Oncology (ICO), Barcelona, Spain. 35Physicians’ Health Study, Divisions of Aging, Cardiovascular Disease, and Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. 36Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA. 37Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. 38Departments of Oncology, Pathology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 39Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden. 40MedStar Research Institute, Georgetown University, Hyattsville, Maryland, USA. 41Nutritional Epidemiology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumoridi Milano, Milan, Italy. 42Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. 43Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA. 44Division of Epidemiology, Public Health and Primary Care, Imperial College London, London, UK. 45Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 46Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 47Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain. 48Synergie-Lyon-Cancer, Inserm, Centre Leon Berard, Lyon, Cedex, France. 49Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. 50Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. 51Division of Research, Kaiser Permanente, Northern California Region, Oakland, California, USA. 52Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. 53Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA. 54These authors contributed equally to this work. Correspondence should be addressed to S.J.C. (chanocks@mail.nih.gov).

Funding Information:
Study participants. Participants were drawn from 12 cohort studies and 8 case-control studies6. The cohort studies are in the Pancreatic Cancer Cohort Consortium GWAS (PanScan1), part of the National Cancer Institute– sponsored Cohort Consortium. The case-control studies are part of the Pancreatic Cancer Case-Control Consortium (PanC4). The cohort studies include the American Cancer Society Cancer Prevention Study-II (CPS-II)32; the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC)33; European Prospective Investigation into Cancer and Nutrition Study (EPIC, which comprises cohorts from Denmark, France, Germany, Great Britain, Greece, Italy, The Netherlands, Spain and Sweden)34; Give us a Clue to Cancer and Heart Disease Study (CLUE II)35; Health Professionals Follow-up Study (HPFS)36; Nurses’ Health Study (NHS)36; New York University Women’s Health Study (NYUWHS)37, Physicians’ Health Study I (PHS I)36; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)38; Shanghai Men’s and Women’s Health Study (SMWHS); Women’s Health Initiative (WHI)39; and the Women’s Health Study (WHS)40 (Supplementary Table 1). The case-control studies include eight case-control studies from the PanC4 consortium, comprising those from the University of Toronto41, University of California San Francisco42, Johns Hopkins University, MD Anderson Cancer Center43, PACIFIC Study of Group Health and Northern California Kaiser Permanente, Memorial Sloan-Kettering Cancer Center44 and Yale University45 and additional cases and controls from the Mayo Clinic Molecular Epidemiology of Pancreatic Cancer Study46 (Supplementary Table 2). Cases were defined as those individuals having primary adenocarcinoma of the exocrine pancreas (ICD-O-3 code C250-C259). Those with non-exocrine pancreatic tumors (histology types 8150, 8151, 8153, 8155 and 8240) were excluded from the study.

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