Oncotarget

Priority Research Papers:

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Mingfeng Zhang _, Zhaoming Wang, Ofure Obazee, Jinping Jia, Erica J. Childs, Jason Hoskins, Gisella Figlioli, Evelina Mocci, Irene Collins, Charles C. Chung, Christopher Hautman, Alan A. Arslan, Laura Beane-Freeman, Paige M. Bracci, Julie Buring, Eric J. Duell, Steven Gallinger, Graham G. Giles, Gary E. Goodman, Phyllis J. Goodman, Aruna Kamineni, Laurence N. Kolonel, Matthew H. Kulke, Núria Malats, Sara H. Olson, Howard D. Sesso, Kala Visvanathan, Emily White, Wei Zheng, Christian C. Abnet, Demetrius Albanes, Gabriella Andreotti, Lauren Brais, H. Bas Bueno-de-Mesquita, Daniela Basso, Sonja I. Berndt, Marie-Christine Boutron-Ruault, Maarten F. Bijlsma, Hermann Brenner, Laurie Burdette, Daniele Campa, Neil E. Caporaso, Gabriele Capurso, Giulia Martina Cavestro, Michelle Cotterchio, Eithne Costello, Joanne Elena, Ugo Boggi, J. Michael Gaziano, Maria Gazouli, Edward L. Giovannucci, Michael Goggins, Myron Gross, Christopher A. Haiman, Manal Hassan, Kathy J. Helzlsouer, Nan Hu, David J. Hunter, Elzbieta Iskierka-Jazdzewska, Mazda Jenab, Rudolf Kaaks, Timothy J. Key, Kay-Tee Khaw, Eric A. Klein, Manolis Kogevinas, Vittorio Krogh, Juozas Kupcinskas, Robert C. Kurtz, Maria T. Landi, Stefano Landi, Loic Le Marchand, Andrea Mambrini, Satu Mannisto, Roger L. Milne, Rachel E. Neale, Ann L. Oberg, Salvatore Panico, Alpa V. Patel, Petra H. M. Peeters, Ulrike Peters, Raffaele Pezzilli, Miquel Porta, Mark Purdue, J. Ramón Quiros, Elio Riboli, Nathaniel Rothman, Aldo Scarpa, Ghislaine Scelo, Xiao-Ou Shu, Debra T. Silverman, Pavel Soucek, Oliver Strobel, Malin Sund, Ewa Małecka-Panas, Philip R. Taylor, Francesca Tavano, Ruth C. Travis, Mark Thornquist, , Geoffrey S. Tobias, Dimitrios Trichopoulos, Yogesh Vashist, Pavel Vodicka, Jean Wactawski-Wende, Nicolas Wentzensen, Herbert Yu, Anne Zeleniuch-Jacquotte, Charles Kooperberg, Harvey A. Risch, Eric J. Jacobs, Donghui Li, Charles Fuchs, Robert Hoover, Patricia Hartge, Stephen J. Chanock, Gloria M. Petersen, Rachael S. Stolzenberg-Solomon, Brian M. Wolpin, Peter Kraft, Alison P. Klein, Federico Canzian and Laufey T. Amundadottir

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Oncotarget. 2016; 7:66328-66343. https://doi.org/10.18632/oncotarget.11041

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Abstract

Mingfeng Zhang 1, Zhaoming Wang 2,3,100, Ofure Obazee 4, Jinping Jia 1, Erica J. Childs 5, Jason Hoskins 1, Gisella Figlioli 4, Evelina Mocci 5, Irene Collins 1, Charles C. Chung 2,3, Christopher Hautman 1, Alan A. Arslan 6,7,8, Laura Beane-Freeman 2, Paige M. Bracci 9, Julie Buring 10,11, Eric J. Duell 12, Steven Gallinger 13, Graham G. Giles 14,15,16, Gary E. Goodman 17, Phyllis J. Goodman 18, Aruna Kamineni 19, Laurence N. Kolonel 20, Matthew H. Kulke 21, Núria Malats 22, Sara H. Olson 23, Howard D. Sesso 24,10,11, Kala Visvanathan 25, Emily White 17,26, Wei Zheng 27,28, Christian C. Abnet 2, Demetrius Albanes 2, Gabriella Andreotti 2, Lauren Brais 21, H. Bas Bueno-de-Mesquita 29,30,31, Daniela Basso 32, Sonja I. Berndt 2, Marie-Christine Boutron-Ruault 33,34,35, Maarten F. Bijlsma 36, Hermann Brenner 37,38,39, Laurie Burdette 2,3, Daniele Campa 40, Neil E. Caporaso 2, Gabriele Capurso 41, Giulia Martina Cavestro 42, Michelle Cotterchio 43,44, Eithne Costello 45, Joanne Elena 46, Ugo Boggi 47, J. Michael Gaziano 10,11,48, Maria Gazouli 49, Edward L. Giovannucci 24,50,51, Michael Goggins 52,53,54, Myron Gross 55, Christopher A. Haiman 56, Manal Hassan 57, Kathy J. Helzlsouer 46, Nan Hu 2, David J. Hunter 58,59,60, Elzbieta Iskierka-Jazdzewska 61, Mazda Jenab 62, Rudolf Kaaks 63, Timothy J. Key 64, Kay-Tee Khaw 65, Eric A. Klein 66, Manolis Kogevinas 67,68,69, Vittorio Krogh 70, Juozas Kupcinskas 71, Robert C. Kurtz 72, Maria T. Landi 2, Stefano Landi 40, Loic Le Marchand 20, Andrea Mambrini 73, Satu Mannisto 74, Roger L. Milne 14,15, Rachel E. Neale 75, Ann L. Oberg 76, Salvatore Panico 77, Alpa V. Patel 78, Petra H. M. Peeters 79,30, Ulrike Peters 17,26, Raffaele Pezzilli 80, Miquel Porta 68,81,82, Mark Purdue 2, J. Ramón Quiros 83, Elio Riboli 30, Nathaniel Rothman 2, Aldo Scarpa 84, Ghislaine Scelo 62, Xiao-Ou Shu 27,28, Debra T. Silverman 2, Pavel Soucek 85, Oliver Strobel 86, Malin Sund 87, Ewa Małecka-Panas 88, Philip R. Taylor 2, Francesca Tavano 89, Ruth C. Travis 64, Mark Thornquist 17, Anne Tjønneland 90, Geoffrey S. Tobias 2, Dimitrios Trichopoulos 24,91,92, Yogesh Vashist 93, Pavel Vodicka 94, Jean Wactawski-Wende 95, Nicolas Wentzensen 2, Herbert Yu 20, Kai Yu 2, Anne Zeleniuch-Jacquotte 7,8, Charles Kooperberg 17, Harvey A. Risch 96, Eric J. Jacobs 78, Donghui Li 57 , Charles Fuchs 21,50, Robert Hoover 2, Patricia Hartge 2, Stephen J. Chanock 2, Gloria M. Petersen 97, Rachael S. Stolzenberg-Solomon 2, Brian M. Wolpin 21, Peter Kraft 24,98, Alison P. Klein 5,99, Federico Canzian 4 and Laufey T. Amundadottir 1

1 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

3 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

4 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

5 Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

6 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA

7 Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA

8 New York University Cancer Institute, New York, New York, USA

9 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA

10 Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

11 Division of Aging, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

12 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain

13 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

14 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia

15 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia

16 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

17 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

18 Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

19 Group Health Research Institute, Seattle, Washington, USA

20 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA

21 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

22 Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain

23 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

24 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

25 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

26 Department of Epidemiology, University of Washington, Seattle, Washington, USA

27 Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

28 Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA

29 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

30 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom

31 Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

32 Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy

33 Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women’s Health Team, F-94805, Villejuif, France

34 University Paris Sud, UMRS 1018, F-94805, Villejuif, France

35 IGR, F-94805, Villejuif, France

36 Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

37 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

38 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany

39 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

40 Department of Biology, University of Pisa, Pisa, Italy

41 Digestive and Liver Disease Unit, ‘Sapienza’ University of Rome, Rome, Italy

42 Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy

43 Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada

44 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

45 National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom

46 Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

47 Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy

48 Massachusetts Veteran’s Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA

49 Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

50 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA

51 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA

52 Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA

53 Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA

54 Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA

55 Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA

56 Preventive Medicine, University of Southern California, Los Angeles, California, USA

57 Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

58 Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

59 Harvard School of Public Health, Boston, Massachusetts, USA

60 Harvard Medical School, Boston, Massachusetts, USA

61 Department of Hematology, Medical University of Łodz, Łodz, Poland

62 International Agency for Research on Cancer (IARC), Lyon, France

63 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

64 Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom

65 School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom

66 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA

67 Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain

68 Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain

69 National School of Public Health, Athens, Greece

70 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

71 Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania

72 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

73 Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy

74 National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland

75 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

76 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA

77 Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy

78 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA

79 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

80 Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Bologna, Italy

81 School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

82 CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

83 Public Health and Participation Directorate, Asturias, Spain

84 ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy

85 Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic

86 Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany

87 Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden

88 Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland

89 Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

90 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark

91 Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece

92 Hellenic Health Foundation, Athens, Greece

93 Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany

94 Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic

95 Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA

96 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA

97 Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA

98 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

99 Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA

100 Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

Correspondence:

Laufey T. Amundadottir, email:

Keywords: pancreatic cancer, GWAS, fine-mapping, imputation, NR5A2

Received: May 16, 2016 Accepted: July 01, 2016 Published: August 01, 2016

Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.


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