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Genetic architectures of proximal and distal colorectal cancer are partly distinct.

About this Publication
Title
Genetic architectures of proximal and distal colorectal cancer are partly distinct.
Pubmed ID
33632709 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Gut. 2021 Jul; Volume 70 (Issue 7): Pages 1325-1334
Authors
Huyghe JR, Harrison TA, Bien SA, Hampel H, Figueiredo JC, Schmit SL, Conti DV, Chen S, Qu C, Lin Y, Barfield R, Baron JA, Cross AJ, Diergaarde B, Duggan D, Harlid S, Imaz L, Kang HM, Levine DM, Perduca V, ...show more Perez-Cornago A, Sakoda LC, Schumacher FR, Slattery ML, Toland AE, van Duijnhoven FJB, Van Guelpen B, Agudo A, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Banbury BL, Bassik MC, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Boutron-Ruault MC, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Caan BJ, Campbell PT, Carr PR, Castells A, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Curtis KR, de la Chapelle A, Easton DF, English DR, Feskens EJM, Gala M, Gallinger SJ, Gauderman WJ, Giles GG, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Jenab M, Jenkins MA, Joshi AD, Keku TO, Kooperberg C, Kühn T, Küry S, Le Marchand L, Lejbkowicz F, Li CI, Li L, Lieb W, Lindblom A, Lindor NM, Männistö S, Markowitz SD, Milne RL, Moreno L, Murphy N, Nassir R, Offit K, Ogino S, Panico S, Parfrey PS, Pearlman R, Pharoah PDP, Phipps AI, Platz EA, Potter JD, Prentice RL, Qi L, Raskin L, Rennert G, Rennert HS, Riboli E, Schafmayer C, Schoen RE, Seminara D, Song M, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Trichopoulou A, Ulrich CM, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Abecasis GR, Nickerson DA, Scacheri PC, Kundaje A, Casey G, Gruber SB, Hsu L, Moreno V, Hayes RB, Newcomb PA, Peters U
Affiliations
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
  • Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
  • Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.
  • Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
  • Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
  • Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
  • Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, Arizona, USA.
...show more
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Public Health Division of Gipuzkoa, Health Department of Basque Country, San Sebastian, Spain.
  • Department of Biostatistics, University of Washington, Seattle, Washington, USA.
  • Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France.
  • Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
  • Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah, USA.
  • Departments of Cancer Biology and Genetics and Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
  • Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
  • Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, 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, Minnesota, 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 Centre (DKFZ), Heidelberg, Germany.
  • Department of Genetics, Stanford University, Stanford, California, USA.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de 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 Health, Salt Lake City, Utah, USA.
  • Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
  • Centre for Research in Epidemiology and Population Health (CESP), Institut pour la Santé et la Recherche Médicale (INSERM) U1018, Université Paris-Saclay, Villejuif, France.
  • 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.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA.
  • Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
  • Division of Clinical Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
  • Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
  • Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
  • The Clalit Health Services, Personalized Genomic Service, Carmel Medical Center, Haifa, Israel.
  • Department of Family Medicine, University of Virginia, Charlottesville, Virginia, 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, Arizona, 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, Ohio, USA.
  • Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
  • Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy.
  • Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
  • Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California, USA.
  • Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • School of Public Health, Imperial College London, London, UK.
  • Department of General Surgery, University Hospital Rostock, Rostock, Germany.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
  • Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, Minnesota, USA.
  • Hellenic Health Foundation, Athens, Greece.
  • Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
  • Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
  • Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA upeters@fhcrc.org.
Abstract

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

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