Genetic architectures of proximal and distal colorectal cancer are partly distinct

doi:10.1136/gutjnl-2020-321534

Meta-Analysis

. 2021 Jul;70(7):1325-1334.

doi: 10.1136/gutjnl-2020-321534. Epub 2021 Feb 25.

Genetic architectures of proximal and distal colorectal cancer are partly distinct

Jeroen R Huyghe¹, Tabitha A Harrison¹, Stephanie A Bien¹, Heather Hampel², Jane C Figueiredo^{3

4}, Stephanie L Schmit⁵, David V Conti⁶, Sai Chen⁷, Conghui Qu¹, Yi Lin¹, Richard Barfield¹, John A Baron⁸, Amanda J Cross⁹, Brenda Diergaarde^{10

11}, David Duggan¹², Sophia Harlid¹³, Liher Imaz¹⁴, Hyun Min Kang⁷, David M Levine¹⁵, Vittorio Perduca^{16

17}, Aurora Perez-Cornago¹⁸, Lori C Sakoda^{1

19}, Fredrick R Schumacher²⁰, Martha L Slattery²¹, Amanda E Toland²², Fränzel J B van Duijnhoven²³, Bethany Van Guelpen¹³, Antonio Agudo²⁴, Demetrius Albanes²⁵, M Henar Alonso^{26

27

28}, Kristin Anderson²⁹, Coral Arnau-Collell³⁰, Volker Arndt³¹, Barbara L Banbury¹, Michael C Bassik³², Sonja I Berndt²⁵, Stéphane Bézieau³³, D Timothy Bishop³⁴, Juergen Boehm³⁵, Heiner Boeing³⁶, Marie-Christine Boutron-Ruault^{17

37}, Hermann Brenner^{31

38

39}, Stefanie Brezina⁴⁰, Stephan Buch⁴¹, Daniel D Buchanan^{42

43

44}, Andrea Burnett-Hartman⁴⁵, Bette J Caan⁴⁶, Peter T Campbell⁴⁷, Prudence R Carr⁴⁸, Antoni Castells³⁰, Sergi Castellví-Bel³⁰, Andrew T Chan^{49

50

51

52

53

54}, Jenny Chang-Claude^{55

56}, Stephen J Chanock²⁵, Keith R Curtis¹, Albert de la Chapelle⁵⁷, Douglas F Easton⁵⁸, Dallas R English^{42

59}, Edith J M Feskens²³, Manish Gala^{49

51}, Steven J Gallinger⁶⁰, W James Gauderman⁶, Graham G Giles^{42

59}, Phyllis J Goodman⁶¹, William M Grady^{62

63}, John S Grove⁶⁴, Andrea Gsur⁴⁰, Marc J Gunter⁶⁵, Robert W Haile⁴, Jochen Hampe⁴¹, Michael Hoffmeister³¹, John L Hopper^{42

66}, Wan-Ling Hsu¹⁵, Wen-Yi Huang²⁵, Thomas J Hudson⁶⁷, Mazda Jenab⁶⁵, Mark A Jenkins⁴², Amit D Joshi^{51

53}, Temitope O Keku⁶⁸, Charles Kooperberg¹, Tilman Kühn⁵⁵, Sébastien Küry³³, Loic Le Marchand⁶⁴, Flavio Lejbkowicz^{69

70

71}, Christopher I Li¹, Li Li⁷², Wolfgang Lieb⁷³, Annika Lindblom^{74

75}, Noralane M Lindor⁷⁶, Satu Männistö⁷⁷, Sanford D Markowitz⁷⁸, Roger L Milne^{42

59}, Lorena Moreno³⁰, Neil Murphy⁶⁵, Rami Nassir⁷⁹, Kenneth Offit^{80

81}, Shuji Ogino^{52

53

82

83}, Salvatore Panico⁸⁴, Patrick S Parfrey⁸⁵, Rachel Pearlman², Paul D P Pharoah⁵⁸, Amanda I Phipps^{1

86}, Elizabeth A Platz⁸⁷, John D Potter¹, Ross L Prentice¹, Lihong Qi⁸⁸, Leon Raskin⁸⁹, Gad Rennert^{70

71

90}, Hedy S Rennert^{70

71

90}, Elio Riboli⁹¹, Clemens Schafmayer⁹², Robert E Schoen⁹³, Daniela Seminara⁹⁴, Mingyang Song^{49

51

95}, Yu-Ru Su¹, Catherine M Tangen⁶¹, Stephen N Thibodeau⁹⁶, Duncan C Thomas⁶, Antonia Trichopoulou^{97

98}, Cornelia M Ulrich³⁵, Kala Visvanathan⁸⁷, Pavel Vodicka^{99

100

101}, Ludmila Vodickova^{99

100

101}, Veronika Vymetalkova^{99

100

101}, Korbinian Weigl^{31

39

102}, Stephanie J Weinstein²⁵, Emily White¹, Alicja Wolk¹⁰³, Michael O Woods¹⁰⁴, Anna H Wu⁶, Goncalo R Abecasis⁷, Deborah A Nickerson¹⁰⁵, Peter C Scacheri¹⁰⁶, Anshul Kundaje^{32

107}, Graham Casey¹⁰⁸, Stephen B Gruber^{109

110}, Li Hsu^{1

15}, Victor Moreno^{26

27

28}, Richard B Hayes¹¹¹, Polly A Newcomb^{1

86}, Ulrike Peters^{112

86}

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
² Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
³ Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
⁴ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁵ Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶ Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
⁷ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁰ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹¹ UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
¹² Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, Arizona, USA.
¹³ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
¹⁴ Public Health Division of Gipuzkoa, Health Department of Basque Country, San Sebastian, Spain.
¹⁵ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
¹⁶ Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France.
¹⁷ Centre for Research in Epidemiology and Population Health (CESP), Institut pour la Santé et la Recherche Médicale (INSERM) U1018, Université Paris-Saclay, Villejuif, France.
¹⁸ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁹ Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
²⁰ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
²¹ Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah, USA.
²² Departments of Cancer Biology and Genetics and Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
²³ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
²⁴ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
²⁶ Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁷ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
²⁸ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
²⁹ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
³⁰ 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.
³¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
³² Department of Genetics, Stanford University, Stanford, California, USA.
³³ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France.
³⁴ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
³⁵ Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah Health, Salt Lake City, Utah, USA.
³⁶ Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
³⁷ Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.
³⁸ Division of Preventive Oncology, German Cancer Research Centre (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁰ Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
⁴¹ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
⁴² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁴³ Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁴ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁴⁵ Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA.
⁴⁶ Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.
⁴⁷ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
⁴⁸ Division of Clinical Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
⁴⁹ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵⁰ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵² Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁵³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁵⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁵⁵ Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
⁵⁶ Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
⁵⁷ Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
⁵⁸ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁶⁰ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
⁶¹ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁶² Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁶³ Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
⁶⁴ University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
⁶⁵ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁶⁶ Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea.
⁶⁷ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁶⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
⁶⁹ The Clalit Health Services, Personalized Genomic Service, Carmel Medical Center, Haifa, Israel.
⁷⁰ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁷¹ Clalit National Cancer Control Center, Haifa, Israel.
⁷² Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA.
⁷³ Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany.
⁷⁴ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁷⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA.
⁷⁷ Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
⁷⁸ Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
⁷⁹ Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
⁸⁰ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁸¹ Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
⁸² Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁸³ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁸⁴ Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy.
⁸⁵ Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
⁸⁶ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁸⁷ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
⁸⁸ Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California, USA.
⁸⁹ Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁹⁰ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁹¹ School of Public Health, Imperial College London, London, UK.
⁹² Department of General Surgery, University Hospital Rostock, Rostock, Germany.
⁹³ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
⁹⁴ Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA.
⁹⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁹⁶ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, Minnesota, USA.
⁹⁷ Hellenic Health Foundation, Athens, Greece.
⁹⁸ WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
⁹⁹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
¹⁰⁰ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
¹⁰¹ Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
¹⁰² Medical Faculty, University of Heidelberg, Heidelberg, Germany.
¹⁰³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁴ Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
¹⁰⁵ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹⁰⁶ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
¹⁰⁷ Department of Computer Science, Stanford University, Stanford, California, USA.
¹⁰⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹⁰⁹ Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
¹¹⁰ City of Hope National Medical Center, Duarte, California, USA.
¹¹¹ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York, USA.
¹¹² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA upeters@fhcrc.org.

PMID: 33632709
PMCID: PMC8223655
DOI: 10.1136/gutjnl-2020-321534

Meta-Analysis

Genetic architectures of proximal and distal colorectal cancer are partly distinct

Jeroen R Huyghe et al. Gut. 2021 Jul.

. 2021 Jul;70(7):1325-1334.

doi: 10.1136/gutjnl-2020-321534. Epub 2021 Feb 25.

Authors

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
² Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
³ Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
⁴ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁵ Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁶ Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
⁷ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁰ Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹¹ UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
¹² Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, Arizona, USA.
¹³ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
¹⁴ Public Health Division of Gipuzkoa, Health Department of Basque Country, San Sebastian, Spain.
¹⁵ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
¹⁶ Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France.
¹⁷ Centre for Research in Epidemiology and Population Health (CESP), Institut pour la Santé et la Recherche Médicale (INSERM) U1018, Université Paris-Saclay, Villejuif, France.
¹⁸ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁹ Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
²⁰ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
²¹ Department of Internal Medicine, University of Utah Health, Salt Lake City, Utah, USA.
²² Departments of Cancer Biology and Genetics and Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
²³ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
²⁴ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
²⁶ Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
²⁷ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
²⁸ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
²⁹ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
³⁰ 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.
³¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
³² Department of Genetics, Stanford University, Stanford, California, USA.
³³ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France.
³⁴ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
³⁵ Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah Health, Salt Lake City, Utah, USA.
³⁶ Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
³⁷ Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France.
³⁸ Division of Preventive Oncology, German Cancer Research Centre (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁹ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁰ Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
⁴¹ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
⁴² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁴³ Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁴⁴ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁴⁵ Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA.
⁴⁶ Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA.
⁴⁷ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
⁴⁸ Division of Clinical Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
⁴⁹ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵⁰ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵¹ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵² Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁵³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁵⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁵⁵ Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
⁵⁶ Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
⁵⁷ Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
⁵⁸ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵⁹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁶⁰ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
⁶¹ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁶² Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
⁶³ Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
⁶⁴ University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
⁶⁵ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
⁶⁶ Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea.
⁶⁷ Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁶⁸ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
⁶⁹ The Clalit Health Services, Personalized Genomic Service, Carmel Medical Center, Haifa, Israel.
⁷⁰ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁷¹ Clalit National Cancer Control Center, Haifa, Israel.
⁷² Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA.
⁷³ Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany.
⁷⁴ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁷⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona, USA.
⁷⁷ Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
⁷⁸ Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
⁷⁹ Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
⁸⁰ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁸¹ Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
⁸² Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
⁸³ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁸⁴ Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II, Naples, Italy.
⁸⁵ Clinical Epidemiology Unit, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
⁸⁶ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁸⁷ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
⁸⁸ Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California, USA.
⁸⁹ Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁹⁰ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁹¹ School of Public Health, Imperial College London, London, UK.
⁹² Department of General Surgery, University Hospital Rostock, Rostock, Germany.
⁹³ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
⁹⁴ Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA.
⁹⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁹⁶ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, MayoClinic, Rochester, Minnesota, USA.
⁹⁷ Hellenic Health Foundation, Athens, Greece.
⁹⁸ WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
⁹⁹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
¹⁰⁰ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
¹⁰¹ Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
¹⁰² Medical Faculty, University of Heidelberg, Heidelberg, Germany.
¹⁰³ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁴ Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
¹⁰⁵ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹⁰⁶ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, Ohio, USA.
¹⁰⁷ Department of Computer Science, Stanford University, Stanford, California, USA.
¹⁰⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹⁰⁹ Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
¹¹⁰ City of Hope National Medical Center, Duarte, California, USA.
¹¹¹ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York, USA.
¹¹² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA upeters@fhcrc.org.

PMID: 33632709
PMCID: PMC8223655
DOI: 10.1136/gutjnl-2020-321534

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.

Keywords: cancer genetics; cancer susceptibility; colon carcinogenesis; colorectal cancer; genetic polymorphisms.

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Conflict of interest statement

Competing interests: None declared.

Figures

**Figure 1**
Primary tumour site-specific associations for the lead single nucleotide polymorphisms (SNPs) of the 13 colorectal cancer risk loci not reported in previous genome-wide association studies. The forest plot shows the (log-additive) OR estimates together with 95% CIs. For clarity, this figure only shows results for the proximal colon, distal colon and rectal cancer case subgroup analyses.

**Figure 2**
Loci showing association with risk of distal colorectal cancer (ie, distal colon+rectal), but attenuated or no evidence for association with proximal colon cancer risk. The forest plot shows the (log-additive) OR estimates for the lead single nucleotide polymorphisms (SNPs) at the loci, together with 95% CIs, from the genome-wide association study meta-analyses of case subgroups defined by primary tumour anatomical subsite for proximal colon, distal colon and rectal. Best model is the best-fitting multinomial logistic regression model according to the Bayesian information criterion (BIC). Models are defined in online supplemental table 2. P_het is the p value from a test for heterogeneity of allelic effects across tumour subsites.

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References

1. American Cancer Society . Cancer statistics center. Available: http://cancerstatisticscenter.cancer.org [Accessed 21 Apr 2020].
1. Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990;113:779–88. 10.7326/0003-4819-113-10-779 - DOI - PubMed
1. Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer 2002;101:403–8. 10.1002/ijc.10635 - DOI - PubMed
1. Carethers JM. One colon lumen but two organs. Gastroenterology 2011;141:411–2. 10.1053/j.gastro.2011.06.029 - DOI - PMC - PubMed
1. Yamauchi M, Lochhead P, Morikawa T, et al. . Colorectal cancer: a tale of two sides or a continuum? Gut 2012;61:794–7. 10.1136/gutjnl-2012-302014 - DOI - PMC - PubMed

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[1] American Cancer Society . Cancer statistics center. Available: http://cancerstatisticscenter.cancer.org [Accessed 21 Apr 2020].

[2] American Cancer Society . Cancer statistics center. Available: http://cancerstatisticscenter.cancer.org [Accessed 21 Apr 2020].

[3] Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990;113:779–88. 10.7326/0003-4819-113-10-779 - DOI - PubMed

[4] Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990;113:779–88. 10.7326/0003-4819-113-10-779 - DOI - PubMed

[5] Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer 2002;101:403–8. 10.1002/ijc.10635 - DOI - PubMed

[6] Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer 2002;101:403–8. 10.1002/ijc.10635 - DOI - PubMed

[7] Carethers JM. One colon lumen but two organs. Gastroenterology 2011;141:411–2. 10.1053/j.gastro.2011.06.029 - DOI - PMC - PubMed

[8] Carethers JM. One colon lumen but two organs. Gastroenterology 2011;141:411–2. 10.1053/j.gastro.2011.06.029 - DOI - PMC - PubMed

[9] Yamauchi M, Lochhead P, Morikawa T, et al. . Colorectal cancer: a tale of two sides or a continuum? Gut 2012;61:794–7. 10.1136/gutjnl-2012-302014 - DOI - PMC - PubMed

[10] Yamauchi M, Lochhead P, Morikawa T, et al. . Colorectal cancer: a tale of two sides or a continuum? Gut 2012;61:794–7. 10.1136/gutjnl-2012-302014 - DOI - PMC - PubMed

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Genetic architectures of proximal and distal colorectal cancer are partly distinct

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Genetic architectures of proximal and distal colorectal cancer are partly distinct

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