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Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk

Yuan F 1 , Hung RJ 2 , Walsh N 3 , Zhang H 1 , Platz EA 4 , Wheeler W 5 Show all authors , Song L 1 , Arslan AA 6 , Beane Freeman LE 1 , Bracci P 7 , Canzian F 8 , Du M 9 , Gallinger S 2 , Giles GG 10 , Goodman PJ 11 , Kooperberg C 12 , Le Marchand L 13 , Neale RE 14 , Rosendahl J 15 , Scelo G 16 , Shu XO 17 , Visvanathan K 4 , White E 18 , Zheng W 17 , Albanes D 1 , Amiano P 19 , Andreotti G 1 , Babic A 20 , Bamlet WR 21 , Berndt SI 1 , Brennan P 16 , Bueno-de-Mesquita B 22 , Buring JE 23 , Campbell PT 24 , Chanock SJ 1 , Fuchs CS 25 , Gaziano JM 26 , Goggins MG 27 , Hackert T 28 , Hartge P 1 , Hassan MM 29 , Holly EA 7 , Hoover RN 1 , Katzke V 30 , Kirsten H 31 , Kurtz RC 32 , Lee IM 23 , Malats N 33 , Milne RL 10 , Murphy N 34 , Ng K 20 , Oberg AL 21 , Porta M 35 , Rabe KG 21 , Real FX 36 , Rothman N 1 , Sesso HD 23 , Silverman DT 1 , Thompson IM 37 , Wactawski-Wende J 38 , Wang X 18 , Wentzensen N 1 , Wilkens LR 13 , Yu H 13 , Zeleniuch-Jacquotte A 39 , Shi J 1 , Duell EJ 40 , Amundadottir LT 1 , Li D 29 , Petersen GM 21 , Wolpin BM 20 , Risch HA 41 , Yu K 1 , Klein AP 4 , Stolzenberg-Solomon R 42

Affiliations 

  • 1 Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland
  • 2 Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, Ontario, Canada
  • 3 National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland
  • 4 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 5 Information Management Services, Inc., Silver Spring, Maryland
  • 6 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA
  • 7 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
  • 8 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 9 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 10 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 11 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 12 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 13 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii
  • 14 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 15 Department of Internal Medicine I, Martin Luther University, Halle, Germany
  • 16 International Agency for Research on Cancer, Lyon, France
  • 17 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 18 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 19 Public Health Division of Gipuzkoa, Ministry of Health of the Basque Government, Donostia-San Sebastian, Spain
  • 20 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 21 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
  • 22 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
  • 23 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 24 Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
  • 25 Yale Cancer Center, New Haven, Connecticut
  • 26 Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  • 27 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland
  • 28 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
  • 29 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
  • 30 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 31 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 32 Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York
  • 33 Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain
  • 34 Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
  • 35 CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
  • 36 CIBERONC, Madrid, Spain
  • 37 CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, Texas
  • 38 Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York
  • 39 Department of Population Health, New York University School of Medicine, New York, New York
  • 40 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain
  • 41 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
  • 42 Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland. rs221z@nih.gov
Cancer Res, 2020 Sep 15;80(18):4004-4013.
PMID: 32641412 DOI: 10.1158/0008-5472.CAN-20-0447

Abstract

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10-6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

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

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