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Discovery of common and rare genetic risk variants for colorectal cancer.

About this Publication
Title
Discovery of common and rare genetic risk variants for colorectal cancer.
Pubmed ID
30510241 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat. Genet. 2019; Volume 51 (Issue 1): Pages 76-87
Authors
Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, Conti DV, Qu C, Jeon J, Edlund CK, Greenside P, Wainberg M, Schumacher FR, Smith JD, Levine DM, Nelson SC, Sinnott-Armstrong NA, Albanes D, Alonso MH, Anderson K, ...show more Arnau-Collell C, Arndt V, Bamia C, Banbury BL, Baron JA, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Chirlaque MD, Cho SH, Connolly CM, Cross AJ, Cuk K, Curtis KR, de la Chapelle A, Doheny KF, Duggan D, Easton DF, Elias SG, Elliott F, English DR, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Forman D, Gala M, Gallinger S, Gauderman WJ, Giles GG, Gillanders E, Gong J, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hampel H, Harlid S, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Hunter DJ, Ibañez-Sanz G, Idos GE, Ingersoll R, Jackson RD, Jacobs EJ, Jenkins MA, Joshi AD, Joshu CE, Keku TO, Key TJ, Kim HR, Kobayashi E, Kolonel LN, Kooperberg C, Kühn T, Küry S, Kweon SS, Larsson SC, Laurie CA, Le Marchand L, Leal SM, Lee SC, Lejbkowicz F, Lemire M, Li CI, Li L, Lieb W, Lin Y, Lindblom A, Lindor NM, Ling H, Louie TL, Männistö S, Markowitz SD, Martín V, Masala G, McNeil CE, Melas M, Milne RL, Moreno L, Murphy N, Myte R, Naccarati A, Newcomb PA, Offit K, Ogino S, Onland-Moret NC, Pardini B, Parfrey PS, Pearlman R, Perduca V, Pharoah PDP, Pinchev M, Platz EA, Prentice RL, Pugh E, Raskin L, Rennert G, Rennert HS, Riboli E, Rodríguez-Barranco M, Romm J, Sakoda LC, Schafmayer C, Schoen RE, Seminara D, Shah M, Shelford T, Shin MH, Shulman K, Sieri S, Slattery ML, Southey MC, Stadler ZK, Stegmaier C, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Thomas SS, Toland AE, Trichopoulou A, Ulrich CM, Van Den Berg DJ, van Duijnhoven FJB, Van Guelpen B, van Kranen H, Vijai J, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Win AK, Wolf CR, Wolk A, Woods MO, Wu AH, Zaidi SH, Zanke BW, Zhang Q, Zheng W, Scacheri PC, Potter JD, Bassik MC, Kundaje A, Casey G, Moreno V, Abecasis GR, Nickerson DA, Gruber SB, Hsu L, Peters U
Affiliations
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
  • Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
  • Department of Computer Science, Stanford University, Stanford, CA, USA.
  • Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • Department of Genome Sciences, University of Washington, Seattle, WA, USA.
  • Department of Biostatistics, University of Washington, Seattle, WA, USA.
...show more
  • Department of Genetics, Stanford University, Stanford, CA, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
  • Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Hellenic Health Foundation, Athens, Greece.
  • Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
  • Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
  • Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
  • Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
  • Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
  • Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
  • Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
  • Department of Hematology-Oncology, Chonnam National University Hospital, Hwasun, South Korea.
  • Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
  • Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
  • Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ, USA.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
  • Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • University of Hawaii Cancer Research Center, Honolulu, HI, USA.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
  • Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
  • Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
  • Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea.
  • Office of Public Health Studies, University of Hawaii Manoa, Honolulu, HI, USA.
  • Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
  • The Clalit Health Services, Personalized Genomic Service, Carmel, Haifa, Israel.
  • Center for Community Health Integration and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
  • Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA.
  • Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
  • Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH, USA.
  • Cancer Risk Factors and Life-Style Epidemiology Unit, Institute of Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
  • USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
  • The Clinical Epidemiology Unit, Memorial University Medical School, Newfoundland, Canada.
  • Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • School of Public Health, Imperial College London, London, UK.
  • Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Oncology Unit, Hillel Yaffe Medical Center, Hadera, Israel.
  • Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Saarland Cancer Registry, Saarbrücken, Germany.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
  • National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
  • Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
  • School of Medicine, University of Dundee, Dundee, Scotland, UK.
  • Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada.
  • Division of Hematology, University of Toronto, Toronto, Ontario, Canada.
  • Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org.
Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

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