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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21</title><author><name sortKey="Zhang, Mingfeng" sort="Zhang, Mingfeng" uniqKey="Zhang M" first="Mingfeng" last="Zhang">Mingfeng Zhang</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Wang, Zhaoming" sort="Wang, Zhaoming" uniqKey="Wang Z" first="Zhaoming" last="Wang">Zhaoming Wang</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> 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</nlm:aff></affiliation><affiliation><nlm:aff id="A100"> Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Obazee, Ofure" sort="Obazee, Ofure" uniqKey="Obazee O" first="Ofure" last="Obazee">Ofure Obazee</name><affiliation><nlm:aff id="A4"> Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Jia, Jinping" sort="Jia, Jinping" uniqKey="Jia J" first="Jinping" last="Jia">Jinping Jia</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Childs, Erica J" sort="Childs, Erica J" uniqKey="Childs E" first="Erica J." last="Childs">Erica J. Childs</name><affiliation><nlm:aff id="A5"> Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hoskins, Jason" sort="Hoskins, Jason" uniqKey="Hoskins J" first="Jason" last="Hoskins">Jason Hoskins</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Figlioli, Gisella" sort="Figlioli, Gisella" uniqKey="Figlioli G" first="Gisella" last="Figlioli">Gisella Figlioli</name><affiliation><nlm:aff id="A4"> Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Mocci, Evelina" sort="Mocci, Evelina" uniqKey="Mocci E" first="Evelina" last="Mocci">Evelina Mocci</name><affiliation><nlm:aff id="A5"> Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Collins, Irene" sort="Collins, Irene" uniqKey="Collins I" first="Irene" last="Collins">Irene Collins</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Chung, Charles C" sort="Chung, Charles C" uniqKey="Chung C" first="Charles C." last="Chung">Charles C. Chung</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> 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</nlm:aff></affiliation></author><author><name sortKey="Hautman, Christopher" sort="Hautman, Christopher" uniqKey="Hautman C" first="Christopher" last="Hautman">Christopher Hautman</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Arslan, Alan A" sort="Arslan, Alan A" uniqKey="Arslan A" first="Alan A." last="Arslan">Alan A. Arslan</name><affiliation><nlm:aff id="A6"> Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A7"> Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A8"> New York University Cancer Institute, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Beane Freeman, Laura" sort="Beane Freeman, Laura" uniqKey="Beane Freeman L" first="Laura" last="Beane-Freeman">Laura Beane-Freeman</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Bracci, Paige M" sort="Bracci, Paige M" uniqKey="Bracci P" first="Paige M." last="Bracci">Paige M. Bracci</name><affiliation><nlm:aff id="A9"> Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA</nlm:aff></affiliation></author><author><name sortKey="Buring, Julie" sort="Buring, Julie" uniqKey="Buring J" first="Julie" last="Buring">Julie Buring</name><affiliation><nlm:aff id="A10"> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A11"> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Duell, Eric J" sort="Duell, Eric J" uniqKey="Duell E" first="Eric J." last="Duell">Eric J. Duell</name><affiliation><nlm:aff id="A12"> Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Gallinger, Steven" sort="Gallinger, Steven" uniqKey="Gallinger S" first="Steven" last="Gallinger">Steven Gallinger</name><affiliation><nlm:aff id="A13"> Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="A14"> Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A15"> Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A16"> Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia</nlm:aff></affiliation></author><author><name sortKey="Goodman, Gary E" sort="Goodman, Gary E" uniqKey="Goodman G" first="Gary E." last="Goodman">Gary E. Goodman</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Goodman, Phyllis J" sort="Goodman, Phyllis J" uniqKey="Goodman P" first="Phyllis J." last="Goodman">Phyllis J. Goodman</name><affiliation><nlm:aff id="A18"> Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Kamineni, Aruna" sort="Kamineni, Aruna" uniqKey="Kamineni A" first="Aruna" last="Kamineni">Aruna Kamineni</name><affiliation><nlm:aff id="A19"> Group Health Research Institute, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Kolonel, Laurence N" sort="Kolonel, Laurence N" uniqKey="Kolonel L" first="Laurence N." last="Kolonel">Laurence N. Kolonel</name><affiliation><nlm:aff id="A20"> Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA</nlm:aff></affiliation></author><author><name sortKey="Kulke, Matthew H" sort="Kulke, Matthew H" uniqKey="Kulke M" first="Matthew H." last="Kulke">Matthew H. Kulke</name><affiliation><nlm:aff id="A21"> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Malats, Nuria" sort="Malats, Nuria" uniqKey="Malats N" first="Núria" last="Malats">Núria Malats</name><affiliation><nlm:aff id="A22"> Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Olson, Sara H" sort="Olson, Sara H" uniqKey="Olson S" first="Sara H." last="Olson">Sara H. Olson</name><affiliation><nlm:aff id="A23"> Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Sesso, Howard D" sort="Sesso, Howard D" uniqKey="Sesso H" first="Howard D." last="Sesso">Howard D. Sesso</name><affiliation><nlm:aff id="A24"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A10"> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A11"> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Visvanathan, Kala" sort="Visvanathan, Kala" uniqKey="Visvanathan K" first="Kala" last="Visvanathan">Kala Visvanathan</name><affiliation><nlm:aff id="A25"> Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="White, Emily" sort="White, Emily" uniqKey="White E" first="Emily" last="White">Emily White</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A26"> Department of Epidemiology, University of Washington, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="A27"> Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A28"> Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Abnet, Christian C" sort="Abnet, Christian C" uniqKey="Abnet C" first="Christian C." last="Abnet">Christian C. Abnet</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Albanes, Demetrius" sort="Albanes, Demetrius" uniqKey="Albanes D" first="Demetrius" last="Albanes">Demetrius Albanes</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Andreotti, Gabriella" sort="Andreotti, Gabriella" uniqKey="Andreotti G" first="Gabriella" last="Andreotti">Gabriella Andreotti</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Brais, Lauren" sort="Brais, Lauren" uniqKey="Brais L" first="Lauren" last="Brais">Lauren Brais</name><affiliation><nlm:aff id="A21"> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Bueno De Mesquita, H Bas" sort="Bueno De Mesquita, H Bas" uniqKey="Bueno De Mesquita H" first="H. Bas" last="Bueno-De-Mesquita">H. Bas Bueno-De-Mesquita</name><affiliation><nlm:aff id="A29"> Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A30"> Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="A31"> Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia</nlm:aff></affiliation></author><author><name sortKey="Basso, Daniela" sort="Basso, Daniela" uniqKey="Basso D" first="Daniela" last="Basso">Daniela Basso</name><affiliation><nlm:aff id="A32"> Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy</nlm:aff></affiliation></author><author><name sortKey="Berndt, Sonja I" sort="Berndt, Sonja I" uniqKey="Berndt S" first="Sonja I." last="Berndt">Sonja I. Berndt</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Boutron Ruault, Marie Christine" sort="Boutron Ruault, Marie Christine" uniqKey="Boutron Ruault M" first="Marie-Christine" last="Boutron-Ruault">Marie-Christine Boutron-Ruault</name><affiliation><nlm:aff id="A33"> Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="A34"> University Paris Sud, UMRS 1018, F-94805, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="A35"> IGR, F-94805, Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Bijlsma, Maarten F" sort="Bijlsma, Maarten F" uniqKey="Bijlsma M" first="Maarten F." last="Bijlsma">Maarten F. Bijlsma</name><affiliation><nlm:aff id="A36"> Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="A37"> Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A38"> Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A39"> German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Burdette, Laurie" sort="Burdette, Laurie" uniqKey="Burdette L" first="Laurie" last="Burdette">Laurie Burdette</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> 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</nlm:aff></affiliation></author><author><name sortKey="Campa, Daniele" sort="Campa, Daniele" uniqKey="Campa D" first="Daniele" last="Campa">Daniele Campa</name><affiliation><nlm:aff id="A40"> Department of Biology, University of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Caporaso, Neil E" sort="Caporaso, Neil E" uniqKey="Caporaso N" first="Neil E." last="Caporaso">Neil E. Caporaso</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Capurso, Gabriele" sort="Capurso, Gabriele" uniqKey="Capurso G" first="Gabriele" last="Capurso">Gabriele Capurso</name><affiliation><nlm:aff id="A41"> Digestive and Liver Disease Unit, ‘Sapienza’ University of Rome, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Cavestro, Giulia Martina" sort="Cavestro, Giulia Martina" uniqKey="Cavestro G" first="Giulia Martina" last="Cavestro">Giulia Martina Cavestro</name><affiliation><nlm:aff id="A42"> Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Cotterchio, Michelle" sort="Cotterchio, Michelle" uniqKey="Cotterchio M" first="Michelle" last="Cotterchio">Michelle Cotterchio</name><affiliation><nlm:aff id="A43"> Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="A44"> Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="Costello, Eithne" sort="Costello, Eithne" uniqKey="Costello E" first="Eithne" last="Costello">Eithne Costello</name><affiliation><nlm:aff id="A45"> National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Elena, Joanne" sort="Elena, Joanne" uniqKey="Elena J" first="Joanne" last="Elena">Joanne Elena</name><affiliation><nlm:aff id="A46"> Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Boggi, Ugo" sort="Boggi, Ugo" uniqKey="Boggi U" first="Ugo" last="Boggi">Ugo Boggi</name><affiliation><nlm:aff id="A47"> Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Gaziano, J Michael" sort="Gaziano, J Michael" uniqKey="Gaziano J" first="J. Michael" last="Gaziano">J. Michael Gaziano</name><affiliation><nlm:aff id="A10"> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A11"> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A48"> Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Gazouli, Maria" sort="Gazouli, Maria" uniqKey="Gazouli M" first="Maria" last="Gazouli">Maria Gazouli</name><affiliation><nlm:aff id="A49"> Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Giovannucci, Edward L" sort="Giovannucci, Edward L" uniqKey="Giovannucci E" first="Edward L." last="Giovannucci">Edward L. Giovannucci</name><affiliation><nlm:aff id="A24"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A50"> Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A51"> Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Goggins, Michael" sort="Goggins, Michael" uniqKey="Goggins M" first="Michael" last="Goggins">Michael Goggins</name><affiliation><nlm:aff id="A52"> Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A53"> Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A54"> Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Gross, Myron" sort="Gross, Myron" uniqKey="Gross M" first="Myron" last="Gross">Myron Gross</name><affiliation><nlm:aff id="A55"> Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA</nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="A56"> Preventive Medicine, University of Southern California, Los Angeles, California, USA</nlm:aff></affiliation></author><author><name sortKey="Hassan, Manal" sort="Hassan, Manal" uniqKey="Hassan M" first="Manal" last="Hassan">Manal Hassan</name><affiliation><nlm:aff id="A57"> Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Helzlsouer, Kathy J" sort="Helzlsouer, Kathy J" uniqKey="Helzlsouer K" first="Kathy J." last="Helzlsouer">Kathy J. Helzlsouer</name><affiliation><nlm:aff id="A46"> Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hu, Nan" sort="Hu, Nan" uniqKey="Hu N" first="Nan" last="Hu">Nan Hu</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hunter, David J" sort="Hunter, David J" uniqKey="Hunter D" first="David J." last="Hunter">David J. Hunter</name><affiliation><nlm:aff id="A58"> Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A59"> Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A60"> Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Iskierka Jazdzewska, Elzbieta" sort="Iskierka Jazdzewska, Elzbieta" uniqKey="Iskierka Jazdzewska E" first="Elzbieta" last="Iskierka-Jazdzewska">Elzbieta Iskierka-Jazdzewska</name><affiliation><nlm:aff id="A61"> Department of Hematology, Medical University of Łodz, Łodz, Poland</nlm:aff></affiliation></author><author><name sortKey="Jenab, Mazda" sort="Jenab, Mazda" uniqKey="Jenab M" first="Mazda" last="Jenab">Mazda Jenab</name><affiliation><nlm:aff id="A62"> International Agency for Research on Cancer (IARC), Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Kaaks, Rudolf" sort="Kaaks, Rudolf" uniqKey="Kaaks R" first="Rudolf" last="Kaaks">Rudolf Kaaks</name><affiliation><nlm:aff id="A63"> Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Key, Timothy J" sort="Key, Timothy J" uniqKey="Key T" first="Timothy J." last="Key">Timothy J. Key</name><affiliation><nlm:aff id="A64"> Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay-Tee" last="Khaw">Kay-Tee Khaw</name><affiliation><nlm:aff id="A65"> School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Klein, Eric A" sort="Klein, Eric A" uniqKey="Klein E" first="Eric A." last="Klein">Eric A. Klein</name><affiliation><nlm:aff id="A66"> Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA</nlm:aff></affiliation></author><author><name sortKey="Kogevinas, Manolis" sort="Kogevinas, Manolis" uniqKey="Kogevinas M" first="Manolis" last="Kogevinas">Manolis Kogevinas</name><affiliation><nlm:aff id="A67"> Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A68"> Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A69"> National School of Public Health, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Krogh, Vittorio" sort="Krogh, Vittorio" uniqKey="Krogh V" first="Vittorio" last="Krogh">Vittorio Krogh</name><affiliation><nlm:aff id="A70"> Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Kupcinskas, Juozas" sort="Kupcinskas, Juozas" uniqKey="Kupcinskas J" first="Juozas" last="Kupcinskas">Juozas Kupcinskas</name><affiliation><nlm:aff id="A71"> Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania</nlm:aff></affiliation></author><author><name sortKey="Kurtz, Robert C" sort="Kurtz, Robert C" uniqKey="Kurtz R" first="Robert C." last="Kurtz">Robert C. Kurtz</name><affiliation><nlm:aff id="A72"> Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Landi, Maria T" sort="Landi, Maria T" uniqKey="Landi M" first="Maria T." last="Landi">Maria T. Landi</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Landi, Stefano" sort="Landi, Stefano" uniqKey="Landi S" first="Stefano" last="Landi">Stefano Landi</name><affiliation><nlm:aff id="A40"> Department of Biology, University of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Marchand, Le Loic" sort="Marchand, Le Loic" uniqKey="Marchand L" first="Le Loic" last="Marchand">Le Loic Marchand</name><affiliation><nlm:aff id="A20"> Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA</nlm:aff></affiliation></author><author><name sortKey="Mambrini, Andrea" sort="Mambrini, Andrea" uniqKey="Mambrini A" first="Andrea" last="Mambrini">Andrea Mambrini</name><affiliation><nlm:aff id="A73"> Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy</nlm:aff></affiliation></author><author><name sortKey="Mannisto, Satu" sort="Mannisto, Satu" uniqKey="Mannisto S" first="Satu" last="Mannisto">Satu Mannisto</name><affiliation><nlm:aff id="A74"> National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="A14"> Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A15"> Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia</nlm:aff></affiliation></author><author><name sortKey="Neale, Rachel E" sort="Neale, Rachel E" uniqKey="Neale R" first="Rachel E." last="Neale">Rachel E. Neale</name><affiliation><nlm:aff id="A75"> Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia</nlm:aff></affiliation></author><author><name sortKey="Oberg, Ann L" sort="Oberg, Ann L" uniqKey="Oberg A" first="Ann L." last="Oberg">Ann L. Oberg</name><affiliation><nlm:aff id="A76"> Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff></affiliation></author><author><name sortKey="Panico, Salvatore" sort="Panico, Salvatore" uniqKey="Panico S" first="Salvatore" last="Panico">Salvatore Panico</name><affiliation><nlm:aff id="A77"> Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Patel, Alpa V" sort="Patel, Alpa V" uniqKey="Patel A" first="Alpa V." last="Patel">Alpa V. Patel</name><affiliation><nlm:aff id="A78"> Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA</nlm:aff></affiliation></author><author><name sortKey="Peeters, Petra H M" sort="Peeters, Petra H M" uniqKey="Peeters P" first="Petra H. M." last="Peeters">Petra H. M. Peeters</name><affiliation><nlm:aff id="A79"> Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A30"> Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Peters, Ulrike" sort="Peters, Ulrike" uniqKey="Peters U" first="Ulrike" last="Peters">Ulrike Peters</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A26"> Department of Epidemiology, University of Washington, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Pezzilli, Raffaele" sort="Pezzilli, Raffaele" uniqKey="Pezzilli R" first="Raffaele" last="Pezzilli">Raffaele Pezzilli</name><affiliation><nlm:aff id="A80"> Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Porta, Miquel" sort="Porta, Miquel" uniqKey="Porta M" first="Miquel" last="Porta">Miquel Porta</name><affiliation><nlm:aff id="A68"> Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A81"> School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A82"> CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Purdue, Mark" sort="Purdue, Mark" uniqKey="Purdue M" first="Mark" last="Purdue">Mark Purdue</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Quiros, J Ram N" sort="Quiros, J Ram N" uniqKey="Quiros J" first="J. Ram N" last="Quiros">J. 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Childs</name><affiliation><nlm:aff id="A5"> Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hoskins, Jason" sort="Hoskins, Jason" uniqKey="Hoskins J" first="Jason" last="Hoskins">Jason Hoskins</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Figlioli, Gisella" sort="Figlioli, Gisella" uniqKey="Figlioli G" first="Gisella" last="Figlioli">Gisella Figlioli</name><affiliation><nlm:aff id="A4"> Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Mocci, Evelina" sort="Mocci, Evelina" uniqKey="Mocci E" first="Evelina" last="Mocci">Evelina Mocci</name><affiliation><nlm:aff id="A5"> Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Collins, Irene" sort="Collins, Irene" uniqKey="Collins I" first="Irene" last="Collins">Irene Collins</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Chung, Charles C" sort="Chung, Charles C" uniqKey="Chung C" first="Charles C." last="Chung">Charles C. Chung</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> 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</nlm:aff></affiliation></author><author><name sortKey="Hautman, Christopher" sort="Hautman, Christopher" uniqKey="Hautman C" first="Christopher" last="Hautman">Christopher Hautman</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Arslan, Alan A" sort="Arslan, Alan A" uniqKey="Arslan A" first="Alan A." last="Arslan">Alan A. Arslan</name><affiliation><nlm:aff id="A6"> Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A7"> Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A8"> New York University Cancer Institute, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Beane Freeman, Laura" sort="Beane Freeman, Laura" uniqKey="Beane Freeman L" first="Laura" last="Beane-Freeman">Laura Beane-Freeman</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Bracci, Paige M" sort="Bracci, Paige M" uniqKey="Bracci P" first="Paige M." last="Bracci">Paige M. Bracci</name><affiliation><nlm:aff id="A9"> Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA</nlm:aff></affiliation></author><author><name sortKey="Buring, Julie" sort="Buring, Julie" uniqKey="Buring J" first="Julie" last="Buring">Julie Buring</name><affiliation><nlm:aff id="A10"> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A11"> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Duell, Eric J" sort="Duell, Eric J" uniqKey="Duell E" first="Eric J." last="Duell">Eric J. Duell</name><affiliation><nlm:aff id="A12"> Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain</nlm:aff></affiliation></author><author><name sortKey="Gallinger, Steven" sort="Gallinger, Steven" uniqKey="Gallinger S" first="Steven" last="Gallinger">Steven Gallinger</name><affiliation><nlm:aff id="A13"> Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="A14"> Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A15"> Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A16"> Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia</nlm:aff></affiliation></author><author><name sortKey="Goodman, Gary E" sort="Goodman, Gary E" uniqKey="Goodman G" first="Gary E." last="Goodman">Gary E. Goodman</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Goodman, Phyllis J" sort="Goodman, Phyllis J" uniqKey="Goodman P" first="Phyllis J." last="Goodman">Phyllis J. Goodman</name><affiliation><nlm:aff id="A18"> Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Kamineni, Aruna" sort="Kamineni, Aruna" uniqKey="Kamineni A" first="Aruna" last="Kamineni">Aruna Kamineni</name><affiliation><nlm:aff id="A19"> Group Health Research Institute, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Kolonel, Laurence N" sort="Kolonel, Laurence N" uniqKey="Kolonel L" first="Laurence N." last="Kolonel">Laurence N. Kolonel</name><affiliation><nlm:aff id="A20"> Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA</nlm:aff></affiliation></author><author><name sortKey="Kulke, Matthew H" sort="Kulke, Matthew H" uniqKey="Kulke M" first="Matthew H." last="Kulke">Matthew H. Kulke</name><affiliation><nlm:aff id="A21"> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Malats, Nuria" sort="Malats, Nuria" uniqKey="Malats N" first="Núria" last="Malats">Núria Malats</name><affiliation><nlm:aff id="A22"> Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Olson, Sara H" sort="Olson, Sara H" uniqKey="Olson S" first="Sara H." last="Olson">Sara H. Olson</name><affiliation><nlm:aff id="A23"> Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Sesso, Howard D" sort="Sesso, Howard D" uniqKey="Sesso H" first="Howard D." last="Sesso">Howard D. Sesso</name><affiliation><nlm:aff id="A24"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A10"> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A11"> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Visvanathan, Kala" sort="Visvanathan, Kala" uniqKey="Visvanathan K" first="Kala" last="Visvanathan">Kala Visvanathan</name><affiliation><nlm:aff id="A25"> Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="White, Emily" sort="White, Emily" uniqKey="White E" first="Emily" last="White">Emily White</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A26"> Department of Epidemiology, University of Washington, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Zheng, Wei" sort="Zheng, Wei" uniqKey="Zheng W" first="Wei" last="Zheng">Wei Zheng</name><affiliation><nlm:aff id="A27"> Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A28"> Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Abnet, Christian C" sort="Abnet, Christian C" uniqKey="Abnet C" first="Christian C." last="Abnet">Christian C. Abnet</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Albanes, Demetrius" sort="Albanes, Demetrius" uniqKey="Albanes D" first="Demetrius" last="Albanes">Demetrius Albanes</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Andreotti, Gabriella" sort="Andreotti, Gabriella" uniqKey="Andreotti G" first="Gabriella" last="Andreotti">Gabriella Andreotti</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Brais, Lauren" sort="Brais, Lauren" uniqKey="Brais L" first="Lauren" last="Brais">Lauren Brais</name><affiliation><nlm:aff id="A21"> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Bueno De Mesquita, H Bas" sort="Bueno De Mesquita, H Bas" uniqKey="Bueno De Mesquita H" first="H. Bas" last="Bueno-De-Mesquita">H. Bas Bueno-De-Mesquita</name><affiliation><nlm:aff id="A29"> Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A30"> Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</nlm:aff></affiliation><affiliation><nlm:aff id="A31"> Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia</nlm:aff></affiliation></author><author><name sortKey="Basso, Daniela" sort="Basso, Daniela" uniqKey="Basso D" first="Daniela" last="Basso">Daniela Basso</name><affiliation><nlm:aff id="A32"> Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy</nlm:aff></affiliation></author><author><name sortKey="Berndt, Sonja I" sort="Berndt, Sonja I" uniqKey="Berndt S" first="Sonja I." last="Berndt">Sonja I. Berndt</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Boutron Ruault, Marie Christine" sort="Boutron Ruault, Marie Christine" uniqKey="Boutron Ruault M" first="Marie-Christine" last="Boutron-Ruault">Marie-Christine Boutron-Ruault</name><affiliation><nlm:aff id="A33"> Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="A34"> University Paris Sud, UMRS 1018, F-94805, Villejuif, France</nlm:aff></affiliation><affiliation><nlm:aff id="A35"> IGR, F-94805, Villejuif, France</nlm:aff></affiliation></author><author><name sortKey="Bijlsma, Maarten F" sort="Bijlsma, Maarten F" uniqKey="Bijlsma M" first="Maarten F." last="Bijlsma">Maarten F. Bijlsma</name><affiliation><nlm:aff id="A36"> Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="A37"> Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A38"> Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="A39"> German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Burdette, Laurie" sort="Burdette, Laurie" uniqKey="Burdette L" first="Laurie" last="Burdette">Laurie Burdette</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3"> 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</nlm:aff></affiliation></author><author><name sortKey="Campa, Daniele" sort="Campa, Daniele" uniqKey="Campa D" first="Daniele" last="Campa">Daniele Campa</name><affiliation><nlm:aff id="A40"> Department of Biology, University of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Caporaso, Neil E" sort="Caporaso, Neil E" uniqKey="Caporaso N" first="Neil E." last="Caporaso">Neil E. Caporaso</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Capurso, Gabriele" sort="Capurso, Gabriele" uniqKey="Capurso G" first="Gabriele" last="Capurso">Gabriele Capurso</name><affiliation><nlm:aff id="A41"> Digestive and Liver Disease Unit, ‘Sapienza’ University of Rome, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Cavestro, Giulia Martina" sort="Cavestro, Giulia Martina" uniqKey="Cavestro G" first="Giulia Martina" last="Cavestro">Giulia Martina Cavestro</name><affiliation><nlm:aff id="A42"> Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Cotterchio, Michelle" sort="Cotterchio, Michelle" uniqKey="Cotterchio M" first="Michelle" last="Cotterchio">Michelle Cotterchio</name><affiliation><nlm:aff id="A43"> Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada</nlm:aff></affiliation><affiliation><nlm:aff id="A44"> Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</nlm:aff></affiliation></author><author><name sortKey="Costello, Eithne" sort="Costello, Eithne" uniqKey="Costello E" first="Eithne" last="Costello">Eithne Costello</name><affiliation><nlm:aff id="A45"> National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Elena, Joanne" sort="Elena, Joanne" uniqKey="Elena J" first="Joanne" last="Elena">Joanne Elena</name><affiliation><nlm:aff id="A46"> Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Boggi, Ugo" sort="Boggi, Ugo" uniqKey="Boggi U" first="Ugo" last="Boggi">Ugo Boggi</name><affiliation><nlm:aff id="A47"> Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Gaziano, J Michael" sort="Gaziano, J Michael" uniqKey="Gaziano J" first="J. Michael" last="Gaziano">J. Michael Gaziano</name><affiliation><nlm:aff id="A10"> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A11"> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A48"> Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Gazouli, Maria" sort="Gazouli, Maria" uniqKey="Gazouli M" first="Maria" last="Gazouli">Maria Gazouli</name><affiliation><nlm:aff id="A49"> Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Giovannucci, Edward L" sort="Giovannucci, Edward L" uniqKey="Giovannucci E" first="Edward L." last="Giovannucci">Edward L. Giovannucci</name><affiliation><nlm:aff id="A24"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A50"> Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A51"> Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Goggins, Michael" sort="Goggins, Michael" uniqKey="Goggins M" first="Michael" last="Goggins">Michael Goggins</name><affiliation><nlm:aff id="A52"> Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A53"> Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A54"> Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Gross, Myron" sort="Gross, Myron" uniqKey="Gross M" first="Myron" last="Gross">Myron Gross</name><affiliation><nlm:aff id="A55"> Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA</nlm:aff></affiliation></author><author><name sortKey="Haiman, Christopher A" sort="Haiman, Christopher A" uniqKey="Haiman C" first="Christopher A." last="Haiman">Christopher A. Haiman</name><affiliation><nlm:aff id="A56"> Preventive Medicine, University of Southern California, Los Angeles, California, USA</nlm:aff></affiliation></author><author><name sortKey="Hassan, Manal" sort="Hassan, Manal" uniqKey="Hassan M" first="Manal" last="Hassan">Manal Hassan</name><affiliation><nlm:aff id="A57"> Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Helzlsouer, Kathy J" sort="Helzlsouer, Kathy J" uniqKey="Helzlsouer K" first="Kathy J." last="Helzlsouer">Kathy J. Helzlsouer</name><affiliation><nlm:aff id="A46"> Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hu, Nan" sort="Hu, Nan" uniqKey="Hu N" first="Nan" last="Hu">Nan Hu</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hunter, David J" sort="Hunter, David J" uniqKey="Hunter D" first="David J." last="Hunter">David J. Hunter</name><affiliation><nlm:aff id="A58"> Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A59"> Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A60"> Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Iskierka Jazdzewska, Elzbieta" sort="Iskierka Jazdzewska, Elzbieta" uniqKey="Iskierka Jazdzewska E" first="Elzbieta" last="Iskierka-Jazdzewska">Elzbieta Iskierka-Jazdzewska</name><affiliation><nlm:aff id="A61"> Department of Hematology, Medical University of Łodz, Łodz, Poland</nlm:aff></affiliation></author><author><name sortKey="Jenab, Mazda" sort="Jenab, Mazda" uniqKey="Jenab M" first="Mazda" last="Jenab">Mazda Jenab</name><affiliation><nlm:aff id="A62"> International Agency for Research on Cancer (IARC), Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Kaaks, Rudolf" sort="Kaaks, Rudolf" uniqKey="Kaaks R" first="Rudolf" last="Kaaks">Rudolf Kaaks</name><affiliation><nlm:aff id="A63"> Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Key, Timothy J" sort="Key, Timothy J" uniqKey="Key T" first="Timothy J." last="Key">Timothy J. Key</name><affiliation><nlm:aff id="A64"> Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Khaw, Kay Tee" sort="Khaw, Kay Tee" uniqKey="Khaw K" first="Kay-Tee" last="Khaw">Kay-Tee Khaw</name><affiliation><nlm:aff id="A65"> School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Klein, Eric A" sort="Klein, Eric A" uniqKey="Klein E" first="Eric A." last="Klein">Eric A. Klein</name><affiliation><nlm:aff id="A66"> Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA</nlm:aff></affiliation></author><author><name sortKey="Kogevinas, Manolis" sort="Kogevinas, Manolis" uniqKey="Kogevinas M" first="Manolis" last="Kogevinas">Manolis Kogevinas</name><affiliation><nlm:aff id="A67"> Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A68"> Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A69"> National School of Public Health, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Krogh, Vittorio" sort="Krogh, Vittorio" uniqKey="Krogh V" first="Vittorio" last="Krogh">Vittorio Krogh</name><affiliation><nlm:aff id="A70"> Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Kupcinskas, Juozas" sort="Kupcinskas, Juozas" uniqKey="Kupcinskas J" first="Juozas" last="Kupcinskas">Juozas Kupcinskas</name><affiliation><nlm:aff id="A71"> Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania</nlm:aff></affiliation></author><author><name sortKey="Kurtz, Robert C" sort="Kurtz, Robert C" uniqKey="Kurtz R" first="Robert C." last="Kurtz">Robert C. Kurtz</name><affiliation><nlm:aff id="A72"> Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Landi, Maria T" sort="Landi, Maria T" uniqKey="Landi M" first="Maria T." last="Landi">Maria T. Landi</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Landi, Stefano" sort="Landi, Stefano" uniqKey="Landi S" first="Stefano" last="Landi">Stefano Landi</name><affiliation><nlm:aff id="A40"> Department of Biology, University of Pisa, Pisa, Italy</nlm:aff></affiliation></author><author><name sortKey="Marchand, Le Loic" sort="Marchand, Le Loic" uniqKey="Marchand L" first="Le Loic" last="Marchand">Le Loic Marchand</name><affiliation><nlm:aff id="A20"> Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA</nlm:aff></affiliation></author><author><name sortKey="Mambrini, Andrea" sort="Mambrini, Andrea" uniqKey="Mambrini A" first="Andrea" last="Mambrini">Andrea Mambrini</name><affiliation><nlm:aff id="A73"> Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy</nlm:aff></affiliation></author><author><name sortKey="Mannisto, Satu" sort="Mannisto, Satu" uniqKey="Mannisto S" first="Satu" last="Mannisto">Satu Mannisto</name><affiliation><nlm:aff id="A74"> National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland</nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="A14"> Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A15"> Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia</nlm:aff></affiliation></author><author><name sortKey="Neale, Rachel E" sort="Neale, Rachel E" uniqKey="Neale R" first="Rachel E." last="Neale">Rachel E. Neale</name><affiliation><nlm:aff id="A75"> Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia</nlm:aff></affiliation></author><author><name sortKey="Oberg, Ann L" sort="Oberg, Ann L" uniqKey="Oberg A" first="Ann L." last="Oberg">Ann L. Oberg</name><affiliation><nlm:aff id="A76"> Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff></affiliation></author><author><name sortKey="Panico, Salvatore" sort="Panico, Salvatore" uniqKey="Panico S" first="Salvatore" last="Panico">Salvatore Panico</name><affiliation><nlm:aff id="A77"> Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Patel, Alpa V" sort="Patel, Alpa V" uniqKey="Patel A" first="Alpa V." last="Patel">Alpa V. Patel</name><affiliation><nlm:aff id="A78"> Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA</nlm:aff></affiliation></author><author><name sortKey="Peeters, Petra H M" sort="Peeters, Petra H M" uniqKey="Peeters P" first="Petra H. M." last="Peeters">Petra H. M. Peeters</name><affiliation><nlm:aff id="A79"> Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A30"> Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Peters, Ulrike" sort="Peters, Ulrike" uniqKey="Peters U" first="Ulrike" last="Peters">Ulrike Peters</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A26"> Department of Epidemiology, University of Washington, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Pezzilli, Raffaele" sort="Pezzilli, Raffaele" uniqKey="Pezzilli R" first="Raffaele" last="Pezzilli">Raffaele Pezzilli</name><affiliation><nlm:aff id="A80"> Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Porta, Miquel" sort="Porta, Miquel" uniqKey="Porta M" first="Miquel" last="Porta">Miquel Porta</name><affiliation><nlm:aff id="A68"> Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A81"> School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain</nlm:aff></affiliation><affiliation><nlm:aff id="A82"> CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Purdue, Mark" sort="Purdue, Mark" uniqKey="Purdue M" first="Mark" last="Purdue">Mark Purdue</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Quiros, J Ram N" sort="Quiros, J Ram N" uniqKey="Quiros J" first="J. Ram N" last="Quiros">J. Ram N Quiros</name><affiliation><nlm:aff id="A83"> Public Health and Participation Directorate, Asturias, Spain</nlm:aff></affiliation></author><author><name sortKey="Riboli, Elio" sort="Riboli, Elio" uniqKey="Riboli E" first="Elio" last="Riboli">Elio Riboli</name><affiliation><nlm:aff id="A30"> Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Rothman, Nathaniel" sort="Rothman, Nathaniel" uniqKey="Rothman N" first="Nathaniel" last="Rothman">Nathaniel Rothman</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Scarpa, Aldo" sort="Scarpa, Aldo" uniqKey="Scarpa A" first="Aldo" last="Scarpa">Aldo Scarpa</name><affiliation><nlm:aff id="A84"> ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy</nlm:aff></affiliation></author><author><name sortKey="Scelo, Ghislaine" sort="Scelo, Ghislaine" uniqKey="Scelo G" first="Ghislaine" last="Scelo">Ghislaine Scelo</name><affiliation><nlm:aff id="A62"> International Agency for Research on Cancer (IARC), Lyon, France</nlm:aff></affiliation></author><author><name sortKey="Shu, Xiao Ou" sort="Shu, Xiao Ou" uniqKey="Shu X" first="Xiao-Ou" last="Shu">Xiao-Ou Shu</name><affiliation><nlm:aff id="A27"> Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A28"> Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA</nlm:aff></affiliation></author><author><name sortKey="Silverman, Debra T" sort="Silverman, Debra T" uniqKey="Silverman D" first="Debra T." last="Silverman">Debra T. Silverman</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Soucek, Pavel" sort="Soucek, Pavel" uniqKey="Soucek P" first="Pavel" last="Soucek">Pavel Soucek</name><affiliation><nlm:aff id="A85"> Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic</nlm:aff></affiliation></author><author><name sortKey="Strobel, Oliver" sort="Strobel, Oliver" uniqKey="Strobel O" first="Oliver" last="Strobel">Oliver Strobel</name><affiliation><nlm:aff id="A86"> Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Sund, Malin" sort="Sund, Malin" uniqKey="Sund M" first="Malin" last="Sund">Malin Sund</name><affiliation><nlm:aff id="A87"> Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden</nlm:aff></affiliation></author><author><name sortKey="Malecka Panas, Ewa" sort="Malecka Panas, Ewa" uniqKey="Malecka Panas E" first="Ewa" last="Małecka-Panas">Ewa Małecka-Panas</name><affiliation><nlm:aff id="A88"> Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland</nlm:aff></affiliation></author><author><name sortKey="Taylor, Philip R" sort="Taylor, Philip R" uniqKey="Taylor P" first="Philip R." last="Taylor">Philip R. Taylor</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Tavano, Francesca" sort="Tavano, Francesca" uniqKey="Tavano F" first="Francesca" last="Tavano">Francesca Tavano</name><affiliation><nlm:aff id="A89"> Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy</nlm:aff></affiliation></author><author><name sortKey="Travis, Ruth C" sort="Travis, Ruth C" uniqKey="Travis R" first="Ruth C." last="Travis">Ruth C. Travis</name><affiliation><nlm:aff id="A64"> Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Thornquist, Mark" sort="Thornquist, Mark" uniqKey="Thornquist M" first="Mark" last="Thornquist">Mark Thornquist</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Tj Nneland, Anne" sort="Tj Nneland, Anne" uniqKey="Tj Nneland A" first="Anne" last="Tj Nneland">Anne Tj Nneland</name><affiliation><nlm:aff id="A90"> Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark</nlm:aff></affiliation></author><author><name sortKey="Tobias, Geoffrey S" sort="Tobias, Geoffrey S" uniqKey="Tobias G" first="Geoffrey S." last="Tobias">Geoffrey S. Tobias</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Trichopoulos, Dimitrios" sort="Trichopoulos, Dimitrios" uniqKey="Trichopoulos D" first="Dimitrios" last="Trichopoulos">Dimitrios Trichopoulos</name><affiliation><nlm:aff id="A24"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A91"> Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece</nlm:aff></affiliation><affiliation><nlm:aff id="A92"> Hellenic Health Foundation, Athens, Greece</nlm:aff></affiliation></author><author><name sortKey="Vashist, Yogesh" sort="Vashist, Yogesh" uniqKey="Vashist Y" first="Yogesh" last="Vashist">Yogesh Vashist</name><affiliation><nlm:aff id="A93"> Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Vodicka, Pavel" sort="Vodicka, Pavel" uniqKey="Vodicka P" first="Pavel" last="Vodicka">Pavel Vodicka</name><affiliation><nlm:aff id="A94"> Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic</nlm:aff></affiliation></author><author><name sortKey="Wactawski Wende, Jean" sort="Wactawski Wende, Jean" uniqKey="Wactawski Wende J" first="Jean" last="Wactawski-Wende">Jean Wactawski-Wende</name><affiliation><nlm:aff id="A95"> Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Wentzensen, Nicolas" sort="Wentzensen, Nicolas" uniqKey="Wentzensen N" first="Nicolas" last="Wentzensen">Nicolas Wentzensen</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Yu, Herbert" sort="Yu, Herbert" uniqKey="Yu H" first="Herbert" last="Yu">Herbert Yu</name><affiliation><nlm:aff id="A20"> Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA</nlm:aff></affiliation></author><author><name sortKey="Yu, Kai" sort="Yu, Kai" uniqKey="Yu K" first="Kai" last="Yu">Kai Yu</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Zeleniuch Jacquotte, Anne" sort="Zeleniuch Jacquotte, Anne" uniqKey="Zeleniuch Jacquotte A" first="Anne" last="Zeleniuch-Jacquotte">Anne Zeleniuch-Jacquotte</name><affiliation><nlm:aff id="A7"> Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A8"> New York University Cancer Institute, New York, New York, USA</nlm:aff></affiliation></author><author><name sortKey="Kooperberg, Charles" sort="Kooperberg, Charles" uniqKey="Kooperberg C" first="Charles" last="Kooperberg">Charles Kooperberg</name><affiliation><nlm:aff id="A17"> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</nlm:aff></affiliation></author><author><name sortKey="Risch, Harvey A" sort="Risch, Harvey A" uniqKey="Risch H" first="Harvey A." last="Risch">Harvey A. Risch</name><affiliation><nlm:aff id="A96"> Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA</nlm:aff></affiliation></author><author><name sortKey="Jacobs, Eric J" sort="Jacobs, Eric J" uniqKey="Jacobs E" first="Eric J." last="Jacobs">Eric J. Jacobs</name><affiliation><nlm:aff id="A78"> Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA</nlm:aff></affiliation></author><author><name sortKey="Li, Donghui" sort="Li, Donghui" uniqKey="Li D" first="Donghui" last="Li">Donghui Li</name><affiliation><nlm:aff id="A57"> Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA</nlm:aff></affiliation></author><author><name sortKey="Fuchs, Charles" sort="Fuchs, Charles" uniqKey="Fuchs C" first="Charles" last="Fuchs">Charles Fuchs</name><affiliation><nlm:aff id="A21"> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A50"> Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Hoover, Robert" sort="Hoover, Robert" uniqKey="Hoover R" first="Robert" last="Hoover">Robert Hoover</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Hartge, Patricia" sort="Hartge, Patricia" uniqKey="Hartge P" first="Patricia" last="Hartge">Patricia Hartge</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Petersen, Gloria M" sort="Petersen, Gloria M" uniqKey="Petersen G" first="Gloria M." last="Petersen">Gloria M. Petersen</name><affiliation><nlm:aff id="A97"> Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA</nlm:aff></affiliation></author><author><name sortKey="Stolzenberg Solomon, Rachael S" sort="Stolzenberg Solomon, Rachael S" uniqKey="Stolzenberg Solomon R" first="Rachael S." last="Stolzenberg-Solomon">Rachael S. Stolzenberg-Solomon</name><affiliation><nlm:aff id="A2"> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Wolpin, Brian M" sort="Wolpin, Brian M" uniqKey="Wolpin B" first="Brian M." last="Wolpin">Brian M. Wolpin</name><affiliation><nlm:aff id="A21"> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Kraft, Peter" sort="Kraft, Peter" uniqKey="Kraft P" first="Peter" last="Kraft">Peter Kraft</name><affiliation><nlm:aff id="A24"> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A98"> Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA</nlm:aff></affiliation></author><author><name sortKey="Klein, Alison P" sort="Klein, Alison P" uniqKey="Klein A" first="Alison P." last="Klein">Alison P. Klein</name><affiliation><nlm:aff id="A5"> Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A99"> Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA</nlm:aff></affiliation></author><author><name sortKey="Canzian, Federico" sort="Canzian, Federico" uniqKey="Canzian F" first="Federico" last="Canzian">Federico Canzian</name><affiliation><nlm:aff id="A4"> Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</nlm:aff></affiliation></author><author><name sortKey="Amundadottir, Laufey T" sort="Amundadottir, Laufey T" uniqKey="Amundadottir L" first="Laufey T." last="Amundadottir">Laufey T. Amundadottir</name><affiliation><nlm:aff id="A1"> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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, <italic>P</italic> = 4.88×10<sup>−15</sup>), rs10094872 at 8q24.21 (OR = 1.15, <italic>P</italic> = 3.22×10<sup>−9</sup>) and rs35226131 at 5p15.33 (OR = 0.71, <italic>P</italic> = 1.70×10<sup>−8</sup>). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (<italic>NR5A2</italic>), chr8q24.21 (<italic>MYC</italic>) and chr5p15.33 (<italic>CLPTM1L</italic>-<italic>TERT</italic>) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (<italic>n</italic> = 10) and tumor (<italic>n</italic> = 8) derived pancreatic tissue samples and observed a marked reduction of <italic>NR5A2</italic> expression (chr1q32.1) in the tumors (fold change -7.6, <italic>P</italic> = 5.7×10<sup>−8</sup>). This finding was validated in a second set of paired (<italic>n</italic> = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three <italic>NR5A2</italic> isoforms -31.3 to -95.7, <italic>P</italic> = 7.5×10<sup>−4</sup>-2.0×10<sup>−3</sup>). 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Society, Ac" uniqKey="Society A">AC Society</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vincent, A" uniqKey="Vincent A">A Vincent</name></author><author><name sortKey="Herman, J" uniqKey="Herman J">J Herman</name></author><author><name sortKey="Schulick, R" uniqKey="Schulick R">R Schulick</name></author><author><name sortKey="Hruban, Rh" uniqKey="Hruban R">RH Hruban</name></author><author><name sortKey="Goggins, M" uniqKey="Goggins M">M Goggins</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Torre, La" uniqKey="Torre L">LA Torre</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Oncotarget</journal-id><journal-id journal-id-type="iso-abbrev">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">ImpactJ</journal-id><journal-title-group><journal-title>Oncotarget</journal-title></journal-title-group><issn pub-type="epub">1949-2553</issn><publisher><publisher-name>Impact Journals LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27579533</article-id><article-id pub-id-type="pmc">5340084</article-id><article-id pub-id-type="publisher-id">11041</article-id><article-id pub-id-type="doi">10.18632/oncotarget.11041</article-id><article-categories><subj-group subj-group-type="heading"><subject>Priority Research Paper</subject></subj-group></article-categories><title-group><article-title>Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 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rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Arslan</surname><given-names>Alan A.</given-names></name><xref ref-type="aff" rid="A6"><sup>6</sup></xref><xref ref-type="aff" rid="A7"><sup>7</sup></xref><xref ref-type="aff" rid="A8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beane-Freeman</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bracci</surname><given-names>Paige M.</given-names></name><xref ref-type="aff" rid="A9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buring</surname><given-names>Julie</given-names></name><xref ref-type="aff" rid="A10"><sup>10</sup></xref><xref ref-type="aff" rid="A11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Duell</surname><given-names>Eric J.</given-names></name><xref ref-type="aff" 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contrib-type="author"><name><surname>Visvanathan</surname><given-names>Kala</given-names></name><xref ref-type="aff" rid="A25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>White</surname><given-names>Emily</given-names></name><xref ref-type="aff" rid="A17"><sup>17</sup></xref><xref ref-type="aff" rid="A26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="A27"><sup>27</sup></xref><xref ref-type="aff" rid="A28"><sup>28</sup></xref></contrib><contrib contrib-type="author"><name><surname>Abnet</surname><given-names>Christian C.</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Albanes</surname><given-names>Demetrius</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib 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contrib-type="author"><name><surname>Iskierka-Jazdzewska</surname><given-names>Elzbieta</given-names></name><xref ref-type="aff" rid="A61"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jenab</surname><given-names>Mazda</given-names></name><xref ref-type="aff" rid="A62"><sup>62</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kaaks</surname><given-names>Rudolf</given-names></name><xref ref-type="aff" rid="A63"><sup>63</sup></xref></contrib><contrib contrib-type="author"><name><surname>Key</surname><given-names>Timothy J.</given-names></name><xref ref-type="aff" rid="A64"><sup>64</sup></xref></contrib><contrib contrib-type="author"><name><surname>Khaw</surname><given-names>Kay-Tee</given-names></name><xref ref-type="aff" rid="A65"><sup>65</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klein</surname><given-names>Eric A.</given-names></name><xref ref-type="aff" rid="A66"><sup>66</sup></xref></contrib><contrib 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contrib-type="author"><name><surname>Landi</surname><given-names>Stefano</given-names></name><xref ref-type="aff" rid="A40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Marchand</surname><given-names>Le Loic</given-names></name><xref ref-type="aff" rid="A20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mambrini</surname><given-names>Andrea</given-names></name><xref ref-type="aff" rid="A73"><sup>73</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mannisto</surname><given-names>Satu</given-names></name><xref ref-type="aff" rid="A74"><sup>74</sup></xref></contrib><contrib contrib-type="author"><name><surname>Milne</surname><given-names>Roger L.</given-names></name><xref ref-type="aff" rid="A14"><sup>14</sup></xref><xref ref-type="aff" rid="A15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neale</surname><given-names>Rachel E.</given-names></name><xref ref-type="aff" 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rid="A91"><sup>91</sup></xref><xref ref-type="aff" rid="A92"><sup>92</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vashist</surname><given-names>Yogesh</given-names></name><xref ref-type="aff" rid="A93"><sup>93</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vodicka</surname><given-names>Pavel</given-names></name><xref ref-type="aff" rid="A94"><sup>94</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wactawski-Wende</surname><given-names>Jean</given-names></name><xref ref-type="aff" rid="A95"><sup>95</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wentzensen</surname><given-names>Nicolas</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Herbert</given-names></name><xref ref-type="aff" rid="A20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Kai</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zeleniuch-Jacquotte</surname><given-names>Anne</given-names></name><xref ref-type="aff" rid="A7"><sup>7</sup></xref><xref ref-type="aff" rid="A8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kooperberg</surname><given-names>Charles</given-names></name><xref ref-type="aff" rid="A17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Risch</surname><given-names>Harvey A.</given-names></name><xref ref-type="aff" rid="A96"><sup>96</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jacobs</surname><given-names>Eric J.</given-names></name><xref ref-type="aff" rid="A78"><sup>78</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Donghui</given-names></name><xref ref-type="aff" rid="A57"><sup>57</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fuchs</surname><given-names>Charles</given-names></name><xref ref-type="aff" rid="A21"><sup>21</sup></xref><xref ref-type="aff" rid="A50"><sup>50</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hoover</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hartge</surname><given-names>Patricia</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chanock</surname><given-names>Stephen J.</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Petersen</surname><given-names>Gloria M.</given-names></name><xref ref-type="aff" rid="A97"><sup>97</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stolzenberg-Solomon</surname><given-names>Rachael S.</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wolpin</surname><given-names>Brian M.</given-names></name><xref ref-type="aff" rid="A21"><sup>21</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kraft</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="A24"><sup>24</sup></xref><xref ref-type="aff" rid="A98"><sup>98</sup></xref></contrib><contrib contrib-type="author"><name><surname>Klein</surname><given-names>Alison P.</given-names></name><xref ref-type="aff" rid="A5"><sup>5</sup></xref><xref ref-type="aff" rid="A99"><sup>99</sup></xref></contrib><contrib contrib-type="author"><name><surname>Canzian</surname><given-names>Federico</given-names></name><xref ref-type="aff" rid="A4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Amundadottir</surname><given-names>Laufey T.</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib></contrib-group><aff id="A1"><sup>1</sup> Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</aff><aff id="A2"><sup>2</sup> Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</aff><aff id="A3"><sup>3</sup> 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</aff><aff id="A4"><sup>4</sup> Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="A5"><sup>5</sup> Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA</aff><aff id="A6"><sup>6</sup> Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA</aff><aff id="A7"><sup>7</sup> Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA</aff><aff id="A8"><sup>8</sup> New York University Cancer Institute, New York, New York, USA</aff><aff id="A9"><sup>9</sup> Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA</aff><aff id="A10"><sup>10</sup> Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</aff><aff id="A11"><sup>11</sup> Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</aff><aff id="A12"><sup>12</sup> Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain</aff><aff id="A13"><sup>13</sup> Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada</aff><aff id="A14"><sup>14</sup> Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia</aff><aff id="A15"><sup>15</sup> Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia</aff><aff id="A16"><sup>16</sup> Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia</aff><aff id="A17"><sup>17</sup> Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</aff><aff id="A18"><sup>18</sup> Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA</aff><aff id="A19"><sup>19</sup> Group Health Research Institute, Seattle, Washington, USA</aff><aff id="A20"><sup>20</sup> Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA</aff><aff id="A21"><sup>21</sup> Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA</aff><aff id="A22"><sup>22</sup> Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain</aff><aff id="A23"><sup>23</sup> Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA</aff><aff id="A24"><sup>24</sup> Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA</aff><aff id="A25"><sup>25</sup> Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA</aff><aff id="A26"><sup>26</sup> Department of Epidemiology, University of Washington, Seattle, Washington, USA</aff><aff id="A27"><sup>27</sup> Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA</aff><aff id="A28"><sup>28</sup> Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA</aff><aff id="A29"><sup>29</sup> Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands</aff><aff id="A30"><sup>30</sup> Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom</aff><aff id="A31"><sup>31</sup> Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia</aff><aff id="A32"><sup>32</sup> Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy</aff><aff id="A33"><sup>33</sup> Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France</aff><aff id="A34"><sup>34</sup> University Paris Sud, UMRS 1018, F-94805, Villejuif, France</aff><aff id="A35"><sup>35</sup> IGR, F-94805, Villejuif, France</aff><aff id="A36"><sup>36</sup> Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands</aff><aff id="A37"><sup>37</sup> Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="A38"><sup>38</sup> Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany</aff><aff id="A39"><sup>39</sup> German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="A40"><sup>40</sup> Department of Biology, University of Pisa, Pisa, Italy</aff><aff id="A41"><sup>41</sup> Digestive and Liver Disease Unit, ‘Sapienza’ University of Rome, Rome, Italy</aff><aff id="A42"><sup>42</sup> Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy</aff><aff id="A43"><sup>43</sup> Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada</aff><aff id="A44"><sup>44</sup> Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada</aff><aff id="A45"><sup>45</sup> National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom</aff><aff id="A46"><sup>46</sup> Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA</aff><aff id="A47"><sup>47</sup> Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy</aff><aff id="A48"><sup>48</sup> Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA</aff><aff id="A49"><sup>49</sup> Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece</aff><aff id="A50"><sup>50</sup> Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA</aff><aff id="A51"><sup>51</sup> Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA</aff><aff id="A52"><sup>52</sup> Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</aff><aff id="A53"><sup>53</sup> Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</aff><aff id="A54"><sup>54</sup> Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA</aff><aff id="A55"><sup>55</sup> Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA</aff><aff id="A56"><sup>56</sup> Preventive Medicine, University of Southern California, Los Angeles, California, USA</aff><aff id="A57"><sup>57</sup> Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA</aff><aff id="A58"><sup>58</sup> Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA</aff><aff id="A59"><sup>59</sup> Harvard School of Public Health, Boston, Massachusetts, USA</aff><aff id="A60"><sup>60</sup> Harvard Medical School, Boston, Massachusetts, USA</aff><aff id="A61"><sup>61</sup> Department of Hematology, Medical University of Łodz, Łodz, Poland</aff><aff id="A62"><sup>62</sup> International Agency for Research on Cancer (IARC), Lyon, France</aff><aff id="A63"><sup>63</sup> Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</aff><aff id="A64"><sup>64</sup> Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom</aff><aff id="A65"><sup>65</sup> School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom</aff><aff id="A66"><sup>66</sup> Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA</aff><aff id="A67"><sup>67</sup> Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain</aff><aff id="A68"><sup>68</sup> Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain</aff><aff id="A69"><sup>69</sup> National School of Public Health, Athens, Greece</aff><aff id="A70"><sup>70</sup> Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy</aff><aff id="A71"><sup>71</sup> Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania</aff><aff id="A72"><sup>72</sup> Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA</aff><aff id="A73"><sup>73</sup> Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy</aff><aff id="A74"><sup>74</sup> National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland</aff><aff id="A75"><sup>75</sup> Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia</aff><aff id="A76"><sup>76</sup> Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA</aff><aff id="A77"><sup>77</sup> Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy</aff><aff id="A78"><sup>78</sup> Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA</aff><aff id="A79"><sup>79</sup> Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands</aff><aff id="A80"><sup>80</sup> Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy</aff><aff id="A81"><sup>81</sup> School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain</aff><aff id="A82"><sup>82</sup> CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain</aff><aff id="A83"><sup>83</sup> Public Health and Participation Directorate, Asturias, Spain</aff><aff id="A84"><sup>84</sup> ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy</aff><aff id="A85"><sup>85</sup> Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic</aff><aff id="A86"><sup>86</sup> Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany</aff><aff id="A87"><sup>87</sup> Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden</aff><aff id="A88"><sup>88</sup> Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland</aff><aff id="A89"><sup>89</sup> Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy</aff><aff id="A90"><sup>90</sup> Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark</aff><aff id="A91"><sup>91</sup> Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece</aff><aff id="A92"><sup>92</sup> Hellenic Health Foundation, Athens, Greece</aff><aff id="A93"><sup>93</sup> Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany</aff><aff id="A94"><sup>94</sup> Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic</aff><aff id="A95"><sup>95</sup> Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA</aff><aff id="A96"><sup>96</sup> Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA</aff><aff id="A97"><sup>97</sup> Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA</aff><aff id="A98"><sup>98</sup> Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA</aff><aff id="A99"><sup>99</sup> Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA</aff><aff id="A100"><sup>100</sup> Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA</aff><author-notes><corresp id="cor1"><bold><italic>Correspondence to:</italic></bold><italic>Laufey T. Amundadottir,</italic><email>amundadottirl@mail.nih.gov</email></corresp></author-notes><pub-date pub-type="collection"><day>11</day><month>10</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>1</day><month>8</month><year>2016</year></pub-date><volume>7</volume><issue>41</issue><fpage>66328</fpage><lpage>66343</lpage><history><date date-type="received"><day>16</day><month>5</month><year>2016</year></date><date date-type="accepted"><day>1</day><month>7</month><year>2016</year></date></history><permissions><copyright-statement>Copyright: © 2016 Zhang et al.</copyright-statement><copyright-year>2016</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>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, <italic>P</italic> = 4.88×10<sup>−15</sup>), rs10094872 at 8q24.21 (OR = 1.15, <italic>P</italic> = 3.22×10<sup>−9</sup>) and rs35226131 at 5p15.33 (OR = 0.71, <italic>P</italic> = 1.70×10<sup>−8</sup>). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (<italic>NR5A2</italic>), chr8q24.21 (<italic>MYC</italic>) and chr5p15.33 (<italic>CLPTM1L</italic>-<italic>TERT</italic>) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (<italic>n</italic> = 10) and tumor (<italic>n</italic> = 8) derived pancreatic tissue samples and observed a marked reduction of <italic>NR5A2</italic> expression (chr1q32.1) in the tumors (fold change -7.6, <italic>P</italic> = 5.7×10<sup>−8</sup>). This finding was validated in a second set of paired (<italic>n</italic> = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three <italic>NR5A2</italic> isoforms -31.3 to -95.7, <italic>P</italic> = 7.5×10<sup>−4</sup>-2.0×10<sup>−3</sup>). 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.</p></abstract><kwd-group><kwd>pancreatic cancer</kwd><kwd>GWAS</kwd><kwd>fine-mapping</kwd><kwd>imputation</kwd><kwd>NR5A2</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>INTRODUCTION</title><p>Although relatively rare, pancreatic tumors are highly lethal. Over 80% of patients present with advanced disease at the time of diagnosis and the five year survival is only 7% [<xref rid="R1" ref-type="bibr">1</xref>, <xref rid="R2" ref-type="bibr">2</xref>]. This disease is currently the third leading cause of cancer deaths in the United States, sixth in Europe and seventh worldwide [<xref rid="R3" ref-type="bibr">3</xref>–<xref rid="R5" ref-type="bibr">5</xref>]. In contrast to most other cancers, mortality rates for pancreatic cancer are not improving [<xref rid="R6" ref-type="bibr">6</xref>, <xref rid="R7" ref-type="bibr">7</xref>]. In the U.S., it is predicted to become the second leading cause of cancer-related deaths by 2030 [<xref rid="R7" ref-type="bibr">7</xref>]. Pancreatic cancer risk has been associated with smoking, obesity, diabetes and pancreatitis [<xref rid="R8" ref-type="bibr">8</xref>]. A small fraction of the familial aggregation of pancreatic cancer can be accounted for by rare, moderately or highly penetrant mutations [<xref rid="R9" ref-type="bibr">9</xref>]. Furthermore, genome-wide association studies (GWAS) have identified common variants at 13 loci associated with risk of pancreatic cancer in European populations and at 5 loci in Asian populations (at the GWAS threshold of <italic>P</italic> < 5.0×10<sup>−8</sup>), or a total of 18 loci [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R15" ref-type="bibr">15</xref>].</p><p>Imputation has proven to be a powerful tool in genome-wide association studies (GWAS) by facilitating investigation of variants not directly assessed on genotyping arrays, the merging of GWAS datasets genotyped on different arrays, and fine-mapping of risk loci [<xref rid="R16" ref-type="bibr">16</xref>]. To discover additional pancreatic cancer susceptibility loci for individuals of European ancestry, we imputed three GWAS datasets including a total of 5,107 cases and 8,845 controls (PanScan I-III, Stage I) [<xref rid="R12" ref-type="bibr">12</xref>]. For replication of promising signals, we first genotyped an additional 1,912 cases and 3,763 controls (PANDoRA; Replication 1), and then further assessed promising signals in a second set of 4,164 cases and 3,792 controls (PanC4; Replication 2). We identified three new susceptibility signals that achieved genome-wide significance for pancreatic cancer risk.</p></sec><sec id="s2"><title>RESULTS</title><p>We conducted imputation of three published pancreatic cancer GWAS datasets performed in individuals of European ancestry, PanScan I, II and III [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R12" ref-type="bibr">12</xref>] using the 1000G (Phase 1, version 3) reference dataset [<xref rid="R17" ref-type="bibr">17</xref>]. We included 9,132,527 genotyped or imputed SNPs with an imputation information (INFO) score >0.5 and minor allele frequency (MAF) >0.01, and performed a fixed effects meta-analysis to combine association results for a total of 5,107 pancreatic cancer cases and 8,845 control subjects [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R12" ref-type="bibr">12</xref>]. Little evidence of systematic inflation due to population stratification was observed (λ = 1.02 for PanScan I+II and λ = 1.07 for PanScan III). We attempted replication of promising findings in two stages. In the first replication stage, we genotyped 15 promising variants in 1,912 pancreatic cancer cases and 3,763 control subjects from the PANcreatic Disease ReseArch (PANDoRA) consortium, a case-control consortium including studies from eight European countries [<xref rid="R18" ref-type="bibr">18</xref>]. In the second replication stage, we assessed the three most significant variants based on the meta-nanalyses results for PanScan I+II, PanScan III and PANDoRA using 4,164 pancreatic cancer cases and 3,792 controls from the Pancreatic Cancer Case-Control Consortium (PanC4), including studies from the U.S., Canada, Europe and Australia [<xref rid="R15" ref-type="bibr">15</xref>]. In total, the discovery and replication stages included 11,183 cases and 16,400 controls (<xref ref-type="supplementary-material" rid="SD2">Supplementary Table 1</xref>).</p><p>In the meta-analysis of PanScan I-III (Stage I), two new variants were identified at genome-wide significance (<italic>P</italic> < 5.0×10<sup>−8</sup>), one on chromosome 1q32.1 (rs2816938: <italic>P</italic> = 1.71×10<sup>−10</sup>, OR = 1.23 95% CI 1.15-1.31) and one on 8q24.21 (rs10094872, <italic>P</italic> = 3.55×10<sup>−8</sup>, OR = 1.18 95% CI 1.11-1.25) (Table <xref ref-type="table" rid="T1">1</xref>, <xref ref-type="supplementary-material" rid="SD2">Supplemental Table 2</xref>). After adjusting the analysis on 1q32.1 for the previously reported GWAS SNP rs3790844 (r<sup>2</sup> = 0.097 in 1000G EUR populations) [<xref rid="R11" ref-type="bibr">11</xref>], the association for rs2816938 remained statistically significant (P<sub>Conditional</sub> = 3.06×10<sup>−6</sup>, OR = 1.17). This was also true for the signal at 8q24.21, marked by rs10094872, after adjusting for the GWAS SNP rs1561927 (r<sup>2</sup> = 0.01 in 1000G EUR) [<xref rid="R12" ref-type="bibr">12</xref>] (P<sub>Conditional</sub> = 1.09×10<sup>−7</sup>, OR = 1.16). The signal at 1q32.1 is located ~11 kb upstream of NR5A2, a gene that encodes a nuclear transcription factor known to play important roles in multiple aspects of pancreatic development and function [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R20" ref-type="bibr">20</xref>]. The SNP at 8q24.21 is located ~28 kb upstream of <italic>MYC</italic>, in a susceptibility locus previously reported for bladder cancer (tagged by rs9642880; r<sup>2</sup> = 0.64 in 1000G EUR) [<xref rid="R21" ref-type="bibr">21</xref>–<xref rid="R23" ref-type="bibr">23</xref>] and ~850 kb upstream of a previously reported pancreatic cancer susceptibility locus [<xref rid="R12" ref-type="bibr">12</xref>].</p><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label><caption><title>Association results for three new pancreatic cancer susceptibility signals</title></caption><table frame="box" rules="all"><thead><tr><th align="center" valign="middle" rowspan="2" colspan="1">Chr</th><th align="center" valign="middle" rowspan="2" colspan="1">Nearest gene(s)<xref ref-type="table-fn" rid="tfn_001"><sup>a</sup></xref></th><th align="center" valign="middle" rowspan="2" colspan="1">SNP</th><th align="center" valign="middle" rowspan="2" colspan="1">Position<xref ref-type="table-fn" rid="tfn_002"><sup>b</sup></xref></th><th align="center" valign="middle" colspan="2" rowspan="1">Alleles<xref ref-type="table-fn" rid="tfn_003"><sup>c</sup></xref></th><th align="center" valign="middle" rowspan="2" colspan="1">INFO<xref ref-type="table-fn" rid="tfn_004"><sup>d</sup></xref></th><th align="center" valign="middle" rowspan="2" colspan="1">Stage</th><th align="center" valign="middle" rowspan="2" colspan="1">Allelic OR (95% CI)</th><th align="center" valign="top" colspan="2" rowspan="1">Minor allele frequency<xref ref-type="table-fn" rid="tfn_005"><sup>e</sup></xref></th><th align="center" valign="top" rowspan="2" colspan="1"><italic>P</italic><xref ref-type="table-fn" rid="tfn_006"><sup>f</sup></xref></th><th align="center" valign="top" colspan="2" rowspan="1">Conditional analysis</th></tr><tr><th align="center" valign="top" rowspan="1" colspan="1">Minor</th><th align="center" valign="top" rowspan="1" colspan="1">Major</th><th align="center" valign="top" rowspan="1" colspan="1">Controls</th><th align="center" valign="top" rowspan="1" colspan="1">Cases</th><th align="center" valign="top" rowspan="1" colspan="1">Conditional <italic>P</italic></th><th align="center" valign="top" rowspan="1" colspan="1">Allelic OR (95% CI)</th></tr></thead><tbody><tr><td align="left" valign="top" rowspan="1" colspan="1">1q32.1</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>NR5A2</italic></td><td align="left" valign="top" rowspan="1" colspan="1">rs2816938</td><td align="center" valign="top" rowspan="1" colspan="1">199,985,368</td><td align="center" valign="top" rowspan="1" colspan="1">A</td><td align="center" valign="top" rowspan="1" colspan="1">T</td><td align="center" valign="top" rowspan="1" colspan="1">1.00</td><td align="center" valign="top" rowspan="1" colspan="1">PanScan I-II</td><td align="center" valign="top" rowspan="1" colspan="1">1.25 (1.16-1.35)</td><td align="center" valign="top" rowspan="1" colspan="1">0.216</td><td align="center" valign="top" rowspan="1" colspan="1">0.255</td><td align="center" valign="top" rowspan="1" colspan="1">1.57 × 10<sup>−8</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">1.00</td><td align="center" valign="top" rowspan="1" colspan="1">PanScan III</td><td align="center" valign="top" rowspan="1" colspan="1">1.19 (1.06-1.33)</td><td align="center" valign="top" rowspan="1" colspan="1">0.231</td><td align="center" valign="top" rowspan="1" colspan="1">0.255</td><td align="center" valign="top" rowspan="1" colspan="1">2.21 × 10<sup>−3</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1">Stage I</td><td align="center" valign="top" rowspan="1" colspan="1">1.23 (1.15-1.31)</td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">1.71 × 10<sup>−10</sup></td><td align="center" valign="top" rowspan="1" colspan="1">3.06 × 10<sup>−6</sup></td><td align="center" valign="top" rowspan="1" colspan="1">1.17 (1.09-1.25)</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">PANDoRA</td><td align="center" valign="top" rowspan="1" colspan="1">1.18 (1.07-1.30)</td><td align="center" valign="top" rowspan="1" colspan="1">0.204</td><td align="center" valign="top" rowspan="1" colspan="1">0.226</td><td align="center" valign="top" rowspan="1" colspan="1">1.12 × 10<sup>−3</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">0.78</td><td align="center" valign="top" rowspan="1" colspan="1">PanC4</td><td align="center" valign="top" rowspan="1" colspan="1">1.16 (1.07-1.26)</td><td align="center" valign="top" rowspan="1" colspan="1">0.167</td><td align="center" valign="top" rowspan="1" colspan="1">0.189</td><td align="center" valign="top" rowspan="1" colspan="1">5.77 × 10<sup>−5</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Combined</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>1.20 (1.15-1.25)</bold></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>4.88 × 10<sup>−15</sup></bold></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">8q24.21</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>MYC</italic></td><td align="left" valign="top" rowspan="1" colspan="1">rs10094872</td><td align="center" valign="top" rowspan="1" colspan="1">128719884</td><td align="center" valign="top" rowspan="1" colspan="1">T</td><td align="center" valign="top" rowspan="1" colspan="1">A</td><td align="center" valign="top" rowspan="1" colspan="1">0.93</td><td align="center" valign="top" rowspan="1" colspan="1">PanScan I-II</td><td align="center" valign="top" rowspan="1" colspan="1">1.19 (1.11-1.28)</td><td align="center" valign="top" rowspan="1" colspan="1">0.350</td><td align="center" valign="top" rowspan="1" colspan="1">0.389</td><td align="center" valign="top" rowspan="1" colspan="1">9.49 × 10<sup>−7</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">0.94</td><td align="center" valign="top" rowspan="1" colspan="1">PanScan III</td><td align="center" valign="top" rowspan="1" colspan="1">1.14 (1.03-1.27)</td><td align="center" valign="top" rowspan="1" colspan="1">0.345</td><td align="center" valign="top" rowspan="1" colspan="1">0.367</td><td align="center" valign="top" rowspan="1" colspan="1">9.27 × 10<sup>−3</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1">Stage I</td><td align="center" valign="top" rowspan="1" colspan="1">1.18 (1.11-1.25)</td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">3.55 × 10<sup>−8</sup></td><td align="center" valign="top" rowspan="1" colspan="1">1.09 × 10<sup>−7</sup></td><td align="center" valign="top" rowspan="1" colspan="1">1.16 (1.13-1.19)</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">PANDoRA</td><td align="center" valign="top" rowspan="1" colspan="1">NA</td><td align="center" valign="top" rowspan="1" colspan="1">NA</td><td align="center" valign="top" rowspan="1" colspan="1">NA</td><td align="center" valign="top" rowspan="1" colspan="1">NA</td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">0.96</td><td align="center" valign="top" rowspan="1" colspan="1">PanC4</td><td align="center" valign="top" rowspan="1" colspan="1">1.10 (1.03-1.18)</td><td align="center" valign="top" rowspan="1" colspan="1">0.359</td><td align="center" valign="top" rowspan="1" colspan="1">0.382</td><td align="center" valign="top" rowspan="1" colspan="1">3.87 × 10<sup>−4</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Combined</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>1.15 (1.10-1.20)</bold></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>3.22×10<sup>−9</sup></bold></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1">5p15.33</td><td align="left" valign="top" rowspan="1" colspan="1"><italic>TERT, CLPTM1L</italic></td><td align="left" valign="top" rowspan="1" colspan="1">rs35226131</td><td align="center" valign="top" rowspan="1" colspan="1">1295373</td><td align="center" valign="top" rowspan="1" colspan="1">T</td><td align="center" valign="top" rowspan="1" colspan="1">C</td><td align="center" valign="top" rowspan="1" colspan="1">0.73</td><td align="center" valign="top" rowspan="1" colspan="1">PanScan I-II</td><td align="center" valign="top" rowspan="1" colspan="1">0.63 (0.52-0.78)</td><td align="center" valign="top" rowspan="1" colspan="1">0.041</td><td align="center" valign="top" rowspan="1" colspan="1">0.029</td><td align="center" valign="top" rowspan="1" colspan="1">1.61 × 10<sup>−5</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">0.79</td><td align="center" valign="top" rowspan="1" colspan="1">PanScan III</td><td align="center" valign="top" rowspan="1" colspan="1">0.65 (0.49-0.87)</td><td align="center" valign="top" rowspan="1" colspan="1">0.036</td><td align="center" valign="top" rowspan="1" colspan="1">0.028</td><td align="center" valign="top" rowspan="1" colspan="1">3.27 × 10<sup>−3</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1">Stage I</td><td align="center" valign="top" rowspan="1" colspan="1">0.64 (0.54-0.76)</td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">1.80 × 10<sup>−7</sup></td><td align="center" valign="top" rowspan="1" colspan="1">3.43 × 10<sup>−7</sup></td><td align="center" valign="top" rowspan="1" colspan="1">0.66 (0.61-0.72)</td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">PANDoRA</td><td align="center" valign="top" rowspan="1" colspan="1">0.83 (0.65-1.05)</td><td align="center" valign="top" rowspan="1" colspan="1">0.033</td><td align="center" valign="top" rowspan="1" colspan="1">0.026</td><td align="center" valign="top" rowspan="1" colspan="1">0.125</td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1">0.87</td><td align="center" valign="top" rowspan="1" colspan="1">PanC4</td><td align="center" valign="top" rowspan="1" colspan="1">0.75 (0.60-0.93)</td><td align="center" valign="top" rowspan="1" colspan="1">0.023</td><td align="center" valign="top" rowspan="1" colspan="1">0.017</td><td align="center" valign="top" rowspan="1" colspan="1">1.01 × 10<sup>−2</sup></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="left" valign="top" rowspan="1" colspan="1"><bold>Combined</bold></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>0.71 (0.63-0.80)</bold></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"><bold>1.70×10<sup>−8</sup></bold></td><td align="left" valign="top" rowspan="1" colspan="1"></td><td align="center" valign="top" rowspan="1" colspan="1"></td></tr></tbody></table><table-wrap-foot><p>Results are shown from an unconditional logistic regression of the genotypes generated in PanScan I, II and III as well as the two replication studies.</p><fn id="tfn_001"><label>a</label><p>Closest RefSeq gene(s).</p></fn><fn id="tfn_002"><label>b</label><p>Position of SNP in NCBI genome build 37 (Hg19).</p></fn><fn id="tfn_003"><label>c</label><p>Minor and major alleles.</p></fn><fn id="tfn_004"><label>d</label><p>Quality of imputation metric.</p></fn><fn id="tfn_005"><label>e</label><p>Minor allele frequencies (MAF) are not listed for meta-analysis results.</p></fn><fn id="tfn_006"><label>f</label><p>1 d.f. score test; Chr: chromosome and band; OR, per-allele OR for the minor allele adjusted for for age, sex, study, arm and significant principal components for PanScan I+II; per-allele OR adjusted for age, sex, geographic region and significant principal components for PanScan III; per-allele OR adjusted for age, sex and study for PANDoRA; per-allele OR adjusted for age, sex, study and significant principal components for PanC4. The number of case and control subjects in the combined set of PanScan I, II, III, PANDoRA and PanC4 were: rs2816938 (11,158/16,343), rs10094872 (9,269/12,635) and rs35226131 (11,143/16,308). Text in bold indicates the combined meta-analysis results. NA: Note that the TaqMan assay for rs10094872 on chr8q24.21 failed manufacturing and was therefore not attempted in the PANDoRA samples.</p></fn></table-wrap-foot></table-wrap><p>A total of 15 promising variants (<italic>P</italic> < 5.0×10<sup>−6</sup>) were selected for replication in 1,912 pancreatic cancer cases and 3,763 control subjects from the European PANDoRA case-control consortium [<xref rid="R18" ref-type="bibr">18</xref>]. After a meta-analysis of PanScan I, II and III and PANDoRA results, the three most promising variants (<xref ref-type="supplementary-material" rid="SD2">Supplemental Table 2</xref>) were carried forward to replication in PanC4 [<xref rid="R15" ref-type="bibr">15</xref>]. The meta-analysis of PanScan I-III with PANDoRA and PanC4 confirmed the signals on chr1q32.1 (<italic>P</italic> = 4.88×10<sup>−15</sup>, OR = 1.20 95% CI 1.15-1.25) and chr8q24.21 (<italic>P</italic> = 3.22×10<sup>−9</sup>, OR = 1.15 95% CI 1.10-1.20). In addition, a new signal in the multicancer region on chr5p15.33, upstream of TERT, was detected (rs35226131, <italic>P</italic> = 1.70×10<sup>−8</sup>, OR = 0.71 95% CI 0.63-0.80) (Table <xref ref-type="table" rid="T1">1</xref>). After conditioning the analysis in PanScan I, II and III on the two reported pancreatic cancer susceptibility loci at 5p15.33, rs36115365 [<xref rid="R24" ref-type="bibr">24</xref>] (tagging the fine-mapped signal for rs401681 [<xref rid="R11" ref-type="bibr">11</xref>] in <italic>CLPTM1L</italic>) and rs2736098 [<xref rid="R12" ref-type="bibr">12</xref>] (tagging the signal in TERT), the signal was still near GWAS significant (P<sub>Unconditional</sub> = 1.80×10<sup>−7</sup>, OR = 0.64; P<sub>Conditional</sub> = 3.43×10<sup>−7</sup>, OR = 0.66). This SNP (rs35226131) is located ~200bps upstream of the transcriptional start site (TSS) of TERT, and marks the least common of the three loci with a MAF of 0.036 in the 1000G EUR populations. The LD between rs35226131 and the previously reported signals is low (r<sup>2</sup> = 0.009 for rs36115365 and r<sup>2</sup> = 0.011 fo rs2736098) in 1000G EUR.</p><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Regional plots for three signals associated with pancreatic cancer risk</title><p>The −log10(<italic>P</italic> value) (Y left axis) for Stage I (PanScan I-III, in gray), PANDoRA (purple) and PanC4 (light blue) was plotted on the genomic coordinates (X axis; NCBI genome build 37). Superimposed blue lines depicts likelihood ratio statistics (right Y axis) estimating putative recombination hotspots in the region. This was performed 5 times, each time utilizing 100 random EUR samples from the 1000 Genomes population (EUR, <italic>n</italic> = 503) (Y right axis). The combined data for Stage I, PANDoRA and PanC4 for three regions: panel <bold>A.</bold> rs2816938 (1q32.1), panel <bold>B.</bold> rs10094872 (8q24.21), and panel <bold>C</bold>: rs3226131 (5p13.33) are shown in red.</p></caption><graphic xlink:href="oncotarget-07-66328-g001a"></graphic><graphic xlink:href="oncotarget-07-66328-g001b"></graphic><graphic xlink:href="oncotarget-07-66328-g001c"></graphic></fig><sec id="s2_1"><title>Bioinformatic analysis of susceptibility alleles and differential expression analysis</title><p>In order to take the first steps towards understanding the functional ramifications at these three new susceptibility signals, we conducted <italic>in silico</italic> bioinformatic analyses using HaploReg and RegulomeDB [<xref rid="R25" ref-type="bibr">25</xref>, <xref rid="R26" ref-type="bibr">26</xref>]. Supporting evidence for putative regulatory function on gene expression was seen for the three loci, particularly for chr1q32.1 and 5p15.33, with open chromatin, modified histones and transcription factor binding in multiple tissues, including those derived from the pancreas and other gastrointestinal tissues (<xref ref-type="supplementary-material" rid="SD2">Supplemental Table 3</xref>). At chr5p15.33, one of the four variants highly correlated with rs35226131 is a missense variant in the second exon of <italic>TERT</italic> (rs61748181: r<sup>2</sup> = 1, D' = 1 in 1000G EUR) whereby the minor allele, associated with reduced risk of pancreatic cancer, changes amino acid 279 from alanine to threonine (A279T).</p><p>We assessed expression quantitative trait loci (eQTL) for the three variants in GTEx [<xref rid="R27" ref-type="bibr">27</xref>] and the nearest genes (<italic>NR5A2</italic> for 1q32.1; <italic>TERT</italic> and <italic>CLPTM1L</italic> for 5p14.33; <italic>MYC</italic> and <italic>PVT1</italic> for 8q24.21; <xref ref-type="supplementary-material" rid="SD2">Supplementary Table 4</xref>) in histologically normal post-mortem pancreatic tissue samples (<italic>n</italic> = 149). The minor allele of the SNP that marks the signal on 8q24.21 (rs10094872) and was associated with increased risk of pancreatic cancer, was associated with decreased <italic>PVT1</italic> expression (β = −0.23, <italic>P</italic> = 0.0053) (<xref ref-type="supplementary-material" rid="SD1">Supplemental Figure 1</xref>). Nominally significant eQTLs (<italic>P</italic> < 0.05) were not seen for <italic>MYC</italic> (<italic>P</italic> = 0.29) or for the SNPs on chr5p15.33 (<italic>P</italic> = 0.91 for <italic>CLPTM1L</italic>; <italic>TERT</italic> was not expressed) or 1q32.1 (<italic>P</italic> = 0.68 for <italic>NR5A2</italic>). We furthermore assessed differential expression of the same genes in pancreatic cell lines (<italic>n</italic> = 9) and pancreatic ductal adenocarcinoma (PDAC) samples (n = 8) as compared with histologically normal pancreatic tissue samples (<italic>n</italic> = 10) by RNAseq [<xref rid="R28" ref-type="bibr">28</xref>] (<xref ref-type="supplementary-material" rid="SD2">Supplemental Tables 5-7</xref>). The most notable differences were seen for <italic>NR5A2</italic> on chr1q32.1 where mRNA expression was markedly lower in pancreatic tumor samples (average fold change -7.6, <italic>P</italic> = 5.7×10<sup>−8</sup>) and cell lines (average fold change -32.7, <italic>P</italic> = 1.5×10<sup>−14</sup>) than in histologically normal pancreatic tissue samples (<xref ref-type="supplementary-material" rid="SD2">Supplemental Table 7</xref>). We further validated this finding in an independent set of paired histologically normal and tumor derived (PDAC) pancreatic tissue samples from 20 individuals by RT-qPCR for three <italic>NR5A2</italic> isoforms and noted decreased expression in tumors for the majority of pairs (average fold change for paired samples was -78.5 for isoform 1, <italic>P</italic> = 2.0×10<sup>−3</sup>; -95.7 fold for isoform 2, <italic>P</italic> = 7.5×10<sup>−4</sup>; -31.3 fold for isoform 3, <italic>P</italic> = 1.5×10<sup>−3</sup>) (Figure <xref ref-type="fig" rid="F2">2</xref>).</p><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Expression of three NR5A2 isoforms in paired histologically normal and tumor derived pancreatic tissue samples</title><p>Blue bars indicate expression in histologically normal samples and red in tumor derived samples. <bold>A.</bold><italic>NR5A2</italic> isoform 1, <bold>B.</bold><italic>NR5A2</italic> isoform 2 and C. <italic>NR5A2</italic> isoform 3. Note that no expression was seen for isoform 1 in either the normal or tumor derived sample from Subject 3. Error bars represent standard deviation from four replicates.</p></caption><graphic xlink:href="oncotarget-07-66328-g002"></graphic></fig></sec><sec id="s2_2"><title>Technical validation of imputed SNPs</title><p>To assess imputation quality, we performed TaqMan genotyping in 678 samples from PanScan I and III (see Materials and Methods). The correlation (r<sup>2</sup>) between the imputed genotypes and those measured by TaqMan was 0.98 for rs2816938 (1q32.1), 0.90 for rs10094872 (8q24.21) and 0.37 for rs35226131 (5p15.33). Due to the lower correlation between imputed and directly assayed genotypes for rs35226131, we performed a second validation in an additional 875 samples, including both rs35226131 as well as the perfectly correlated coding SNP on 5p15.33 mentioned above, rs61748181. The imputed-genotyped r<sup>2</sup> for rs35226131 improved to 0.44 in the second validation set, and was 0.55 for rs61748181. Genotype concordance for the most likely imputed genotypes and directly assayed genotypes (see Materials and Methods) for rs35226131 improved from 86.4% in the first validation set to 94.4% in the second set, and was 96.2% for rs61748181 in the second set. Since rs61748181 was directly genotyped in one of the replication studies (PanC4), we performed a meta-analysis of PanScan I-III (OR = 0.62 95% CI 0.52-0.75, <italic>P</italic> = 5.37×10<sup>−7</sup>) and PanC4 (OR = 0.67 95% CI 0.55-0.85, <italic>P</italic> = 1.91×10<sup>−4</sup>) data. This revealed a highly significant association for rs61748181 (OR = 0.64 95% CI 0.56-0.74, <italic>P</italic> = 1.28×10<sup>−10</sup>) that was stronger than that seen for rs35226131 (OR = 0.68 95% CI 0.59-0.79, <italic>P</italic> = 1.91×10<sup>−8</sup>). These results suggest that the association results at this potentially new pancreatic cancer risk locus are reliable.</p></sec></sec><sec id="s3"><title>DISCUSSION</title><p>In this study, we performed imputation across three pancreatic cancer GWAS datasets, namely PanScan I, II and III [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R12" ref-type="bibr">12</xref>], using 1000G reference data. Through replication of promising variants in individuals from two independent pancreatic cancer case-control consortia, PANDoRA and PanC4, we identified three new GWAS significant risk signals for pancreatic cancer. They are independent signals in previously established pancreatic cancer risk loci on chromosomes 1q32.1, 5p15.33 and 8q24.21, as per conditional analysis, supporting their importance for pancreatic cancer risk.</p><p>The signal on 1q32.1 is located in <italic>NR5A2,</italic> a gene that encodes nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor important for pancreatic development and adult function in the pancreas, liver, intestine and ovary, where it regulates cholesterol synthesis, bile acid homeostasis and steroidogenesis [<xref rid="R19" ref-type="bibr">19</xref>, <xref rid="R20" ref-type="bibr">20</xref>]. NR5A2 is an important regulator of exocrine function in the adult pancreas where it maintains homeostasis and promotes regeneration of acinar cells after inflammation caused by chemically induced pancreatitis, and protects the pancreas from <italic>KRAS</italic> driven pre-neoplastic changes [<xref rid="R29" ref-type="bibr">29</xref>–<xref rid="R31" ref-type="bibr">31</xref>]. Other studies have indicated a growth inducing role for NR5A2 in pancreatic cancer [<xref rid="R32" ref-type="bibr">32</xref>, <xref rid="R33" ref-type="bibr">33</xref>]. Highly correlated variants (r2>0.7) span ~25 kb on chr1q32.1 from ~11 kb upstream of the TSS to within the second intron of the gene. We observed significantly lower mRNA expression of <italic>NR5A2</italic> in the majority of pancreatic tumors and cell lines tested compared with histologically normal pancreatic tissue samples, indicating a possible role for reduced <italic>NR5A2</italic> expression in pancreatic cancer. Although an expression QTL was not observed in GTEx data, the relationship between the two currently known pancreatic cancer risk loci on 1q32.1 and <italic>NR5A2</italic> expression remains to be studied in greater detail.</p><p>The tag SNP on 8q24.21 is located ~28 kb upstream of <italic>MYC</italic> at an established bladder cancer risk locus [<xref rid="R21" ref-type="bibr">21</xref>–<xref rid="R23" ref-type="bibr">23</xref>] that is ~850 kb upstream of our previously reported pancreatic cancer susceptibility locus [<xref rid="R12" ref-type="bibr">12</xref>]. Multiple independent susceptibility loci on 8q24.21, distributed over a 2 Mb region, are known to influence risk of bladder, breast, prostate, colorectal, lung, ovarian, pancreatic, renal cancer, glioma and chronic lymphocytic leukemia (CLL) [<xref rid="R34" ref-type="bibr">34</xref>–<xref rid="R38" ref-type="bibr">38</xref>]. Deregulated expression of MYC, a transcription factor that regulates multiple aspects of cell growth and proliferation, occurs in a broad range of human tumors [<xref rid="R39" ref-type="bibr">39</xref>]. Although the proximity of rs10094872 to <italic>MYC</italic> indicates that it may be the most likely target gene, 8q24.21 is known for long range chromosomal interactions, and additional candidate genes, including <italic>PVT1</italic> (183 kb), <italic>POU5F1B</italic> (290 kb), <italic>CCAT2</italic> (305 kb) and <italic>MIR1205</italic>-<italic>MIR1208</italic> (253-442 kb), could be involved [<xref rid="R40" ref-type="bibr">40</xref>–<xref rid="R44" ref-type="bibr">44</xref>]. Several of the 8q24.21 risk loci interact with the <italic>MYC</italic> and <italic>PVT1</italic> promoters through long range chromosomal interaction, and allele-specific effects on gene expression have been reported for both genes [<xref rid="R42" ref-type="bibr">42</xref>, <xref rid="R45" ref-type="bibr">45</xref>]. An expression <italic>QTL</italic> for <italic>MYC</italic> has been described for the bladder cancer risk locus in histologically normal bladder samples from Chinese subjects, albeit from a very small set [<xref rid="R46" ref-type="bibr">46</xref>], but not in adipose or blood tissue samples from European subjects [<xref rid="R22" ref-type="bibr">22</xref>]. We noted an eQTL for rs10094872 and <italic>PVT1</italic> expression in pancreatic tissue samples in GTEx, indicating that <italic>PVT1</italic> may be a target gene for this locus. Replication of these findings is required in independent sample sets. <italic>PVT1</italic> encodes a long noncoding RNA that is often amplified and upregulated along with <italic>MYC</italic> across multiple cancers. Recently, it has been shown to increase MYC protein levels and potentiate its activity [<xref rid="R47" ref-type="bibr">47</xref>]. In pancreatic cancer, <italic>PVT1</italic> expression is associated with gemcitabine sensitivity in human pancreatic cancer cells and may be associated with poor prognosis [<xref rid="R47" ref-type="bibr">47</xref>–<xref rid="R49" ref-type="bibr">49</xref>].</p><p>The signal on chr5p15.33 lies in another multicancer susceptibility region reported by GWAS for bladder cancer, breast cancer, chronic lymphocytic leukemia, glioma, lung cancer, melanoma, non-melanoma skin cancer, ovarian cancer, pancreatic cancer, prostate cancer and testicular germ cell cancer [<xref rid="R11" ref-type="bibr">11</xref>, <xref rid="R12" ref-type="bibr">12</xref>, <xref rid="R23" ref-type="bibr">23</xref>, <xref rid="R37" ref-type="bibr">37</xref>, <xref rid="R50" ref-type="bibr">50</xref>–<xref rid="R60" ref-type="bibr">60</xref>]. For the 6 independent susceptibility loci that have been identified in the <italic>TERT-CLPTM1L</italic> gene region, the same alleles are associated with an increased risk for some cancers but decreased risk of others [<xref rid="R24" ref-type="bibr">24</xref>, <xref rid="R60" ref-type="bibr">60</xref>, <xref rid="R61" ref-type="bibr">61</xref>]. Two independent pancreatic cancer susceptibility loci have previously been identified on chr5p15.33 through GWAS [<xref rid="R11" ref-type="bibr">11</xref>, <xref rid="R12" ref-type="bibr">12</xref>, <xref rid="R24" ref-type="bibr">24</xref>]. The first one, described in PanScan II [<xref rid="R11" ref-type="bibr">11</xref>] was marked by an intronic SNP (rs401681) in <italic>CLPTM1L</italic> that has since been fine-mapped to rs451360 (and a set of highly correlated variants including rs36115365) [<xref rid="R24" ref-type="bibr">24</xref>]. A second independent signal on 5p15.33 was identified in PanScan III, tagged by a synonymous SNP (rs2736098) in the second exon of <italic>TERT</italic> [<xref rid="R12" ref-type="bibr">12</xref>]. Recently, a third risk locus, marked by rs2853677, was identified in this genomic region through a candidate gene analysis of the <italic>TERT</italic> and <italic>TERC</italic> genes [<xref rid="R62" ref-type="bibr">62</xref>]; however this variant did not attain GWAS significance in our study (PanScan I-III, <italic>P</italic> = 4.2×10<sup>−4</sup>). The <italic>TERT</italic> gene encodes the catalytic subunit of telomerase, known for its critical role in maintaining telomere ends and the increased telomerase activity frequently seen in human cancers [<xref rid="R63" ref-type="bibr">63</xref>–<xref rid="R65" ref-type="bibr">65</xref>]. Telomere-independent functions for TERT include regulation of gene expression, cell survival, epithelial to mesenchymal transition (EMT) and mitochondrial function [<xref rid="R66" ref-type="bibr">66</xref>]. The neighboring gene encodes cleft lip and palate associated transmembrane 1 like (CLPTM1L) protein that promotes growth and survival in pancreatic and lung cancer, respectively, and is overexpressed in some cancers [<xref rid="R67" ref-type="bibr">67</xref>–<xref rid="R69" ref-type="bibr">69</xref>]. The SNP (rs35226131) that marks the new risk signal on 5p15.33 reported here, and highly correlated variants, are located in the <italic>TERT</italic> promoter (~200-500 bp upstream of the TSS) and could potentially influence its expression. Additionally, it is perfectly correlated with a nonsynonomous variant in <italic>TERT</italic> (rs61748181, A279T) that was recently reported as a novel lung adenocarcinoma risk locus by deep sequencing and direct genotyping of 5,164 cases and 5,716 controls of European ancestry [<xref rid="R70" ref-type="bibr">70</xref>]. The threonine substitution at this amino acid in TERT negatively influences telomere length and proliferation in esophageal cancer cell lines compared with alanine, and leads to reduced Wnt signaling through destabilization of complexes containing TERT, transcription activator BRG-1 and β-catenin [<xref rid="R71" ref-type="bibr">71</xref>]. As the TERT-279T variant is protective for pancreatic cancer in our study, and for lung cancer [<xref rid="R70" ref-type="bibr">70</xref>], the underlying mechanism at this locus may relate to increased TERT activity via canonical and/or non-canonical TERT pathways. This hypothesis needs to be formally investigated by future molecular studies.</p><p>In conclusion, through imputation of three existing GWAS datasets and replication in two independent case-control consortia, we identified three new susceptibility signals for pancreatic cancer in populations of European ancestry. They are located in genomic regions previously reported by GWAS of pancreatic cancer, further supporting their importance for pancreatic cancer risk. Further work is required to identify target genes and explain the underlying biological mechanisms.</p></sec><sec sec-type="methods" id="s4"><title>MATERIALS AND METHODS</title><sec id="s4_1"><title>Study participants</title><p>Participants were drawn from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium (PanC4) and include individuals from 17 cohort and 11 case-control studies genotyped in three previous GWAS phases, namely PanScan I, PanScan II and PanScan III [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R12" ref-type="bibr">12</xref>]. Two replication cohorts were included, the PANDoRA consortium [<xref rid="R18" ref-type="bibr">18</xref>] (Replication I) and the Pancreatic Cancer Case-Control Consortium (PanC4) [<xref rid="R15" ref-type="bibr">15</xref>] (Replication 2). Cases were defined as individuals diagnosed with adenocarcinoma of the pancreas.</p><p>Each study obtained informed consent from study participants and approval from its Institutional Review Board (IRB) including IRB certification permitting data sharing in accordance with the NIH Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS). The PanScan and PanC4 GWAS data are available through dbGAP (accession numbers phs000206.v5.p3 and phs000648.v1.p1, respectively).</p></sec><sec id="s4_2"><title>Genotyping, imputation and association analysis</title><p>GWAS genotyping was performed at the Cancer Genomics Research Laboratory (CGR) of the National Cancer Institute (NCI) of the National Institutes of Health (NIH) using the Illumina HumanHap series arrays (Illumina HumanHap550 Infinium II, Human 610-Quad) for PanScan I-II, and the Illumina Omni series arrays (OmniExpress, Omni1M, Omni2.5 and Omni5M) for PanScan III [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R12" ref-type="bibr">12</xref>]. The 1000 Genomes (1000G) Phase 1, Release 3 [<xref rid="R17" ref-type="bibr">17</xref>] reference dataset was used to impute the PanScan I-III GWAS datasets using IMPUTE2 [<xref rid="R72" ref-type="bibr">72</xref>] as previously described [<xref rid="R12" ref-type="bibr">12</xref>, <xref rid="R24" ref-type="bibr">24</xref>]. Due to the large overlap of variants on genotyping arrays for PanScan I and II, these datasets were imputed and analyzed together. The PanScan III data was imputed and analyzed separately. For quality control, variants were excluded based on: 1) completion rate < 90%; 2) MAF < 0.01; 3) Hardy-Weinberg Proportion <italic>P</italic> value < 1×10<sup>−6</sup>; 4) low quality imputation score (IMPUTE 2 INFO score < 0.5). After quality control, 9,132,527 SNPs in 5,107 pancreatic cancer cases and 8,845 controls of European ancestry were included in the analysis. The association analysis was performed using SNPTEST [<xref rid="R73" ref-type="bibr">73</xref>] based on probabilistic genotypes from IMPUTE2 [<xref rid="R72" ref-type="bibr">72</xref>] using the same adjustments for study, geographical region, age, sex and population substructure as were used in PanScan [<xref rid="R10" ref-type="bibr">10</xref>–<xref rid="R12" ref-type="bibr">12</xref>]. The score test of the log additive genetic effect was used. A meta-analysis of data from PanScan I & II with PanScan III was performed using the fixed-effects inverse-variance method based on β estimates and standard errors. Heterogeneity was not observed for the SNPs identified as GWAS significant or suggestive in the combined study (P<sub>heterogeneity</sub> ≥0.30)</p><p>The estimated inflation of the test statistic, λ, was 1.02 for PanScan I+II and 1.07 for PanScan III, respectively (using variants with MAF>0.01 and INFO>0.5) [<xref rid="R74" ref-type="bibr">74</xref>].</p></sec><sec id="s4_3"><title>Replication</title><p>Fifteen variants giving promising signals (<italic>P</italic> < 5.0×10<sup>−6</sup>) were selected for replication in the PANDoRA consortium (Replication 1) [<xref rid="R18" ref-type="bibr">18</xref>]. Genotyping was performed by custom TaqMan genotyping assays (Applied Biosystems) at the German Cancer Research Center (DKFZ) in Heidelberg, Germany in 3,343 pancreatic cancer cases and 4,998 controls, of which 2,820 cases and 3,909 controls had complete demographic and clinical data and did not overlap with other study samples. Duplicate quality control samples (n = 541 pairs) showed 99.67% genotype concordance. Samples on a few plates were not genotyped for all variants. Unfortunately these plates contained more cases than controls. We excluded 908 cases and 146 controls, either with low genotyping completion rate (< 80%) or not genotyped, resulting in a total of 1,912 cases and 3,763 controls in the final analyses. The association analysis for PANDoRA was adjusted for age, gender and study in the same manner as previously described [<xref rid="R12" ref-type="bibr">12</xref>].</p><p>Three variants from the meta-analysis of PanScan and PANDoRA were then selected for a second replication in the Pancreatic Cancer Case-Control Consortium (PanC4) [<xref rid="R15" ref-type="bibr">15</xref>] (Replication 2). Genotyping for PanC4 had previously been performed at the Johns Hopkins Center for Inherited Disease Research (CIDR) using the IlluminaHumanOmniExpressExome-8v1 array followed by imputation using 100G Phase 3, version 1 [<xref rid="R75" ref-type="bibr">75</xref>] and IMPUTE2. Association analysis was performed in 4,164 pancreatic cancer cases and 3,792 control subjects of European ancestry as previously described [<xref rid="R15" ref-type="bibr">15</xref>]. Variants at 3 chromosomal locations were extracted from the results and meta-analyses conducted as described above. Heterogeneity between studies was assessed using the Cochran's Q-test. IMPUTE2 information scores were 0.78 (rs2816938), 0.96 (rs10094872) and 0.87 (rs35226131) for the three reported variants.</p><p>Recombination hotspots for association plots were generated as previously described using SequenceLDhot (10-12). The recombination hotspot inference was performed 5 times, each time utilizing a hundred random sampled EUR from the 1000 Genomes (EUR, n = 503). The linkage disequilibrium heatmap was prepared using the 1000 Genomes Phase 3 EUR data (n = 505, CEU+FIN+GBR+IBS+TSI), and snp.plotter R software package [<xref rid="R76" ref-type="bibr">76</xref>].</p></sec><sec id="s4_4"><title>Validation of imputation accuracy</title><p>Imputation accuracy was assessed by direct TaqMan genotyping or Sanger sequencing. TaqMan genotyping assays (ABI, Foster City, CA) were optimized for three SNPs (rs2816938 on 1q32.1, rs35226131 on 5p15.33 and rs10094872 on 8q24.21) in the independent regions. In an analysis of 678 samples from PanScan I and III [<xref rid="R10" ref-type="bibr">10</xref>, <xref rid="R12" ref-type="bibr">12</xref>, <xref rid="R77" ref-type="bibr">77</xref>], the allelic r<sup>2</sup> measured between imputed and assayed genotypes [<xref rid="R78" ref-type="bibr">78</xref>] were 0.98, 0.37 and 0.90, respectively. A second validation in an additional 875 samples from PanScan I included two perfectly correlated SNPs on 5p15.33, rs35226131 and rs61748181; the allelic r<sup>2</sup> in this set was 0.44 and 0.55, respectively. We also assessed concordance between the most likely imputed genotypes and directly measured genotypes as follows: samples with imputed allelic dosage ranging from 0-0.5 were designated as being of the homozygous common genotype; samples ranging from 0.51-1.5 as being of the heterozygous genotype and samples ranging from 1.51-2.0 as being of the rare homozygous genotype.</p></sec><sec id="s4_5"><title>Bioinformatic analysis of functional potential</title><p>HaploReg v4.1 (<ext-link ext-link-type="uri" xlink:href="http://www.broadinstitute.org/mammals/haploreg/haploreg.php">http://www.broadinstitute.org/mammals/haploreg/haploreg.php</ext-link>) was used to annotate functional and regulatory potential of the most significant germline variants at each locus as well as highly correlated variants (r<sup>2</sup>>0.7) that mark each of the regions identified [<xref rid="R25" ref-type="bibr">25</xref>]. RegulomeDB (<ext-link ext-link-type="uri" xlink:href="http://regulomedb.org/">http://regulomedb.org/</ext-link>) was used to assess and score regulatory potential of variants in each locus [<xref rid="R26" ref-type="bibr">26</xref>]. Expression quantitative trait locus (eQTL) effects were assessed using the Genotype-Tissue Expression Project (GTEx) database (<ext-link ext-link-type="uri" xlink:href="http://www.gtexportal.org/home/">http://www.gtexportal.org/home/</ext-link>) for pancreatic tissues (<italic>n</italic> = 149 samples) [<xref rid="R27" ref-type="bibr">27</xref>].</p></sec><sec id="s4_6"><title>Analysis of gene expression</title><p>Gene expression was assessed for five genes that are closest to the reported variants on chromosomes 1q32.1 (<italic>NR5A2</italic>), 5p15.33 (<italic>TERT</italic> and <italic>CLPTM1L</italic>), and 8q24.21 (<italic>MYC</italic> and <italic>PVT1</italic>). We first assessed differential expression of these genes in pancreatic tumor samples (PDAC, n = 8), histologically normal (non-malignant) pancreatic tissue samples (n = 10), and pancreatic cell lines (n = 9) by RNA-sequencing as described previously [<xref rid="R28" ref-type="bibr">28</xref>]. We compared gene expression in tumors and cell lines to histologically normal pancreatic tissue samples by EdgeR analysis [<xref rid="R28" ref-type="bibr">28</xref>]. P-values represent an exact test of the differential expression of each gene in histologically normal and tumor derived samples using normalized read counts in EdgeR.</p><p>We also assessed the expression of one of these genes (<italic>NR5A2</italic>) in a second independent tissue sample set that included 20 fresh frozen paired histologically normal pancreatic samples (adjacent to tumor) and pancreatic ductal adenocarcinoma (PDAC) tumor samples. RNA samples were isolated from fresh frozen tissues and reverse transcribed to cDNA as previously described [<xref rid="R28" ref-type="bibr">28</xref>]. Three <italic>NR5A2</italic> isoforms (isoform 1: NM_205860, isoform 2: NM_003822, and isoform 3: uc009wzh.3) were tested using TaqMan gene expression assays (Thermo Fisher Scientific, isoform 1: Hs00894632_m1, isoform2: Hs00892375_m1 and a custom assay, for isoform 3 forward primer: 5′CTTTTCGCCGGAGTTGAAT3′; reverse primer: 5′GTCCGGAAGCCCAGCA3′; probe: 5′ CTGTGCTGCCCGTGTCC3′) and a 7900HT system (ABI). Each reaction was run in triplicate and analyzed according to the ΔΔCt method using <italic>B2M</italic> (Hs99999907_m1), <italic>GAPDH</italic> (Hs99999905_m1) and <italic>PPIA</italic> (Hs99999904_m1) as housekeeping genes. <italic>P</italic>-values represent two-sided T-tests of the difference in expression between histologically normal and tumor derived samples.</p><p>All tissue samples were obtained from the Mayo Clinic in Rochester, MN. The project was approved by the Institutional Review Boards of the Mayo Clinic and the NIH. Nine pancreatic cancer cell lines (AsPC-1, BxPC-3, Hs766T, SU.86.86, SW1990, CFPAC-1, Capan-1, PANC-1, MIA PaCa-2) were purchased from ATCC and cultured as recommended (<ext-link ext-link-type="uri" xlink:href="http://www.atcc.com/">http://www.ATCC.com</ext-link>). The cell lines were tested for authentication with a panel of short tandem repeats (STR) using the Identifiler kit (Life Technologies) and compared with the ATCC and the DSMZ (German Collection of Microorganisms and Cell Cultures) STR Profile Databases. All cell lines matched the listed profiles.</p></sec></sec><sec sec-type="supplementary-material" id="s5"><title>SUPPLEMENTARY MATERIAL FIGURE</title><supplementary-material content-type="local-data" id="SD1"><media mimetype="application" mime-subtype="pdf" xlink:href="oncotarget-07-66328-s001.pdf" orientation="portrait" xlink:type="simple" id="d35e3302" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD2"><media mimetype="application" mime-subtype="docx" xlink:href="oncotarget-07-66328-s002.docx" orientation="portrait" xlink:type="simple" id="d35e3304" position="anchor"></media></supplementary-material></sec></body><back><ack><p>The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the <xref ref-type="supplementary-material" rid="SD1">Supplemental Materials</xref>.</p></ack><fn-group><fn fn-type="COI-statement"><p><bold>CONFLICTS OF INTEREST</bold></p><p>The authors do not have any potential conflicts of interest.</p></fn></fn-group><ref-list><title>REFERENCES</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Society</surname><given-names>AC</given-names></name></person-group><article-title>Cancer Facts and Figures</article-title><source>Int J BiolSci</source><year>2016</year><volume>12</volume><fpage>273</fpage><lpage>282</lpage></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group 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