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A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer

Zhong J 1 , Jermusyk A 1 , Wu L 2 , Hoskins JW 1 , Collins I 1 , Mocci E 3 Show all authors , Zhang M 1 , Song L 4 , Chung CC 4 , Zhang T 4 , Xiao W 5 , Albanes D 4 , Andreotti G 4 , Arslan AA 6 , Babic A 7 , Bamlet WR 8 , Beane-Freeman L 4 , Berndt S 4 , Borgida A 9 , Bracci PM 10 , Brais L 7 , Brennan P 11 , Bueno-de-Mesquita B 12 , Buring J 13 , Canzian F 14 , Childs EJ 3 , Cotterchio M 15 , Du M 16 , Duell EJ 17 , Fuchs C 18 , Gallinger S 9 , Gaziano JM 13 , Giles GG 19 , Giovannucci E 7 , Goggins M 20 , Goodman GE 21 , Goodman PJ 22 , Haiman C 23 , Hartge P 4 , Hasan M 24 , Helzlsouer KJ 25 , Holly EA 26 , Klein EA 27 , Kogevinas M 28 , Kurtz RJ 29 , LeMarchand L 30 , Malats N 31 , Männistö S 32 , Milne R 19 , Neale RE 33 , Ng K 7 , Obazee O 14 , Oberg AL 8 , Orlow I 16 , Patel AV 34 , Peters U 21 , Porta M 35 , Rothman N 4 , Scelo G 11 , Sesso HD 13 , Severi G 36 , Sieri S 37 , Silverman D 4 , Sund M 38 , Tjønneland A 39 , Thornquist MD 21 , Tobias GS 4 , Trichopoulou A , Van Den Eeden SK 40 , Visvanathan K 41 , Wactawski-Wende J 42 , Wentzensen N 4 , White E 21 , Yu H 30 , Yuan C 7 , Zeleniuch-Jacquotte A 43 , Hoover R 4 , Brown K 1 , Kooperberg C 21 , Risch HA 44 , Jacobs EJ 45 , Li D 46 , Yu K 4 , Shu XO 2 , Chanock SJ 4 , Wolpin BM 7 , Stolzenberg-Solomon RZ 4 , Chatterjee N 4 , Klein AP 3 , Smith JP 47 , Kraft P 48 , Shi J 4 , Petersen GM 8 , Zheng W 2 , Amundadottir LT 1

Affiliations 

  • 1 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • 2 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
  • 3 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
  • 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • 5 National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
  • 6 Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • 8 Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
  • 9 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 10 Department of Epidemiology and Biostatistics, University of California, CA, USA
  • 11 International Agency for Research on Cancer, Lyon, France
  • 12 Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment, BA, Bilthoven, The Netherlands
  • 13 Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA
  • 14 Genomic Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
  • 15 Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada
  • 16 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • 17 Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona, Spain
  • 18 Yale Cancer Center, New Haven, CT, USA
  • 19 Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia
  • 20 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
  • 21 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 22 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 23 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 24 Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 25 Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • 26 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
  • 27 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
  • 28 ISGlobal, Centre for Research in Environmental Epidemiology, Barcelona, Spain
  • 29 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • 30 Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 31 Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center, Madrid, Spain
  • 32 Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland
  • 33 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 34 Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
  • 35 CIBER Epidemiología y Salud Pública, Barcelona, Spain
  • 36 Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France
  • 37 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
  • 38 Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
  • 39 Danish Cancer Society Research Center, Copenhagen, Denmark
  • 40 Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
  • 41 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
  • 42 Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA
  • 43 Department of Population Health, New York University School of Medicine, New York, NY, USA
  • 44 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
  • 45 Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA
  • 46 Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 47 Department of Medicine, Georgetown University, Washington, DC, USA
  • 48 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
J Natl Cancer Inst, 2020 Oct 01;112(10):1003-1012.
PMID: 31917448 DOI: 10.1093/jnci/djz246

Abstract

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown.

METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples).

RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction.

CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

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

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