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

Zhang M 1 , Wang Z 2 , Obazee O 3 , Jia J 1 , Childs EJ 4 , Hoskins J 1 Show all authors , Figlioli G 3 , Mocci E 4 , Collins I 1 , Chung CC 2 , Hautman C 1 , Arslan AA 5 , Beane-Freeman L 2 , Bracci PM 6 , Buring J 7 , Duell EJ 8 , Gallinger S 9 , Giles GG 10 , Goodman GE 11 , Goodman PJ 12 , Kamineni A 13 , Kolonel LN 14 , Kulke MH 15 , Malats N 16 , Olson SH 17 , Sesso HD 18 , Visvanathan K 19 , White E 11 , Zheng W 20 , Abnet CC 2 , Albanes D 2 , Andreotti G 2 , Brais L 15 , Bueno-de-Mesquita HB 21 , Basso D 22 , Berndt SI 2 , Boutron-Ruault MC 23 , Bijlsma MF 24 , Brenner H 25 , Burdette L 2 , Campa D 26 , Caporaso NE 2 , Capurso G 27 , Cavestro GM 28 , Cotterchio M 29 , Costello E 30 , Elena J 31 , Boggi U 32 , Gaziano JM 7 , Gazouli M 33 , Giovannucci EL 18 , Goggins M 34 , Gross M 35 , Haiman CA 36 , Hassan M 37 , Helzlsouer KJ 31 , Hu N 2 , Hunter DJ 38 , Iskierka-Jazdzewska E 39 , Jenab M 40 , Kaaks R 41 , Key TJ 42 , Khaw KT 43 , Klein EA 44 , Kogevinas M 45 , Krogh V 46 , Kupcinskas J 47 , Kurtz RC 48 , Landi MT 2 , Landi S 26 , Le Marchand L 14 , Mambrini A 49 , Mannisto S 50 , Milne RL 10 , Neale RE 51 , Oberg AL 52 , Panico S 53 , Patel AV 54 , Peeters PH 55 , Peters U 11 , Pezzilli R 56 , Porta M 57 , Purdue M 2 , Quiros JR 58 , Riboli E 59 , Rothman N 2 , Scarpa A 60 , Scelo G 40 , Shu XO 20 , Silverman DT 2 , Soucek P 61 , Strobel O 62 , Sund M 63 , Małecka-Panas E 64 , Taylor PR 2 , Tavano F 65 , Travis RC 42 , Thornquist M 11 , Tjønneland A 66 , Tobias GS 2 , Trichopoulos D 18 , Vashist Y 67 , Vodicka P 68 , Wactawski-Wende J 69 , Wentzensen N 2 , Yu H 14 , Yu K 2 , Zeleniuch-Jacquotte A 70 , Kooperberg C 71 , Risch HA 72 , Jacobs EJ 54 , Li D 37 , Fuchs C 15 , Hoover R 2 , Hartge P 2 , Chanock SJ 2 , Petersen GM 73 , Stolzenberg-Solomon RS 2 , Wolpin BM 15 , Kraft P 18 , Klein AP 4 , Canzian F 3 , Amundadottir LT 1

Affiliations 

  • 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 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 4 Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  • 5 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA
  • 6 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
  • 7 Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  • 8 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain
  • 9 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 10 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 11 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  • 12 Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  • 13 Group Health Research Institute, Seattle, Washington, USA,
  • 14 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
  • 15 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  • 16 Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain
  • 17 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  • 18 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  • 19 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
  • 20 Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  • 21 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 22 Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy,
  • 23 Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France
  • 24 Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • 25 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 26 Department of Biology, University of Pisa, Pisa, Italy
  • 27 Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy
  • 28 Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 29 Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada
  • 30 National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom
  • 31 Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  • 32 Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy
  • 33 Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • 34 Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA
  • 35 Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
  • 36 Preventive Medicine, University of Southern California, Los Angeles, California, USA
  • 37 Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
  • 38 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  • 39 Department of Hematology, Medical University of Łodz, Łodz, Poland
  • 40 International Agency for Research on Cancer (IARC), Lyon, France
  • 41 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 42 Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom
  • 43 School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
  • 44 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
  • 45 Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain
  • 46 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 47 Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
  • 48 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  • 49 Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy
  • 50 National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland
  • 51 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 52 Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  • 53 Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy
  • 54 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA
  • 55 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
  • 56 Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy
  • 57 Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain
  • 58 Public Health and Participation Directorate, Asturias, Spain
  • 59 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
  • 60 ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
  • 61 Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
  • 62 Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany
  • 63 Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden
  • 64 Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland
  • 65 Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
  • 66 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
  • 67 Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany
  • 68 Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
  • 69 Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA
  • 70 Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
  • 71 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,
  • 72 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
  • 73 Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
Oncotarget, 2016 Oct 11;7(41):66328-66343.
PMID: 27579533 DOI: 10.18632/oncotarget.11041

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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