title: Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.
abstract: Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Mingfeng
authors: M
authors: Zhang
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|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.|Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Zhaoming
authors: Z
authors: Wang
authors: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Ofure
authors: O
authors: Obazee
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Jinping
authors: J
authors: Jia
authors: Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Erica J
authors: EJ
authors: Childs
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Jason
authors: J
authors: Hoskins
authors: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Gisella
authors: G
authors: Figlioli
authors: Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Evelina
authors: E
authors: Mocci
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Irene
authors: I
authors: Collins
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|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.
authors: Charles C
authors: CC
authors: Chung
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Christopher
authors: C
authors: Hautman
authors: Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA.|Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA.|New York University Cancer Institute, New York, New York, USA,.
authors: Alan A
authors: AA
authors: Arslan
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Laura
authors: L
authors: Beane-Freeman
authors: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA.
authors: Paige M
authors: PM
authors: Bracci
authors: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Julie
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authors: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Steven
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authors: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.|Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
authors: Graham G
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authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
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authors: Laurence N
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authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Matthew H
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authors: Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain.
authors: Núria
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authors: Malats
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors: Sara H
authors: SH
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authors: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.|Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Howard D
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authors: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
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authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.
authors: Emily
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authors: Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Wei
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Gabriella
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authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Lauren
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authors: Brais
authors: Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.|Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors: H Bas
authors: HB
authors: Bueno-de-Mesquita
authors: Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy,.
authors: Daniela
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authors: Basso
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Sonja I
authors: SI
authors: Berndt
authors: Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France.|University Paris Sud, UMRS 1018, F-94805, Villejuif, France.|IGR, F-94805, Villejuif, France.
authors: Marie-Christine
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authors: Boutron-Ruault
authors: Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Maarten F
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authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Hermann
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authors: Brenner
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|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.
authors: Laurie
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authors: Burdette
authors: Department of Biology, University of Pisa, Pisa, Italy.
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Neil E
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authors: Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy.
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authors: Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada.|Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
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authors: National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
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authors: Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Joanne
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authors: Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.
authors: Ugo
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authors: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA.
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authors: Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors: Maria
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authors: Gazouli
authors: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.|Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Edward L
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authors: Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.|Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.|Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA.
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authors: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
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authors: Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain.|Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain.|National School of Public Health, Athens, Greece.
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authors: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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authors: Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
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authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Department of Biology, University of Pisa, Pisa, Italy.
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authors: Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy.
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authors: National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland.
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authors: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.|Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
authors: Roger L
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authors: Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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authors: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
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authors: Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy.
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authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors: Petra H M
authors: PH
authors: Peeters
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.
authors: Ulrike
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authors: Peters
authors: Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
authors: Raffaele
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authors: Pezzilli
authors: Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain.|School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.|CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors: Miquel
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authors: Porta
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Public Health and Participation Directorate, Asturias, Spain.
authors: J Ramón
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authors: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
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authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: Xiao-Ou
authors: XO
authors: Shu
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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authors: DT
authors: Silverman
authors: Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors: Pavel
authors: P
authors: Soucek
authors: Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Oliver
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authors: Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden.
authors: Malin
authors: M
authors: Sund
authors: Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland.
authors: Ewa
authors: E
authors: Małecka-Panas
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Philip R
authors: PR
authors: Taylor
authors: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors: Francesca
authors: F
authors: Tavano
authors: Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
authors: Ruth C
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authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Mark
authors: M
authors: Thornquist
authors: Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
authors: Anne
authors: A
authors: Tjønneland
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Geoffrey S
authors: GS
authors: Tobias
authors: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.|Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece.|Hellenic Health Foundation, Athens, Greece.
authors: Dimitrios
authors: D
authors: Trichopoulos
authors: Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany.
authors: Yogesh
authors: Y
authors: Vashist
authors: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors: Pavel
authors: P
authors: Vodicka
authors: Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA.
authors: Jean
authors: J
authors: Wactawski-Wende
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Nicolas
authors: N
authors: Wentzensen
authors: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors: Herbert
authors: H
authors: Yu
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Kai
authors: K
authors: Yu
authors: Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA.|New York University Cancer Institute, New York, New York, USA.
authors: Anne
authors: A
authors: Zeleniuch-Jacquotte
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,.
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authors: C
authors: Kooperberg
authors: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
authors: Harvey A
authors: HA
authors: Risch
authors: Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.
authors: Eric J
authors: EJ
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authors: Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
authors: Donghui
authors: D
authors: Li
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
authors: Charles
authors: C
authors: Fuchs
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Robert
authors: R
authors: Hoover
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Patricia
authors: P
authors: Hartge
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Stephen J
authors: SJ
authors: Chanock
authors: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
authors: Gloria M
authors: GM
authors: Petersen
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Rachael S
authors: RS
authors: Stolzenberg-Solomon
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Brian M
authors: BM
authors: Wolpin
authors: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.
authors: Peter
authors: P
authors: Kraft
authors: Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors: Alison P
authors: AP
authors: Klein
authors: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Federico
authors: F
authors: Canzian
authors: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Laufey T
authors: LT
authors: Amundadottir
mesh_terms: D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D066264:Datasets as Topic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
keywords: GWAS; NR5A2	; fine-mapping; imputation; pancreatic cancer