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.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia USA

Broad Institute of Harvard and MIT Cambridge Massachusetts USA

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology Group University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

Cancer Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford UK

Cancer Prevention and Control Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill North Carolina USA

Center for Public Health Genomics University of Virginia Charlottesville Virginia USA

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Centre for Research in Epidemiology and Population Health U1018 Université Paris Saclay Villejuif France

Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

CIBER Epidemiología y Salud Pública Madrid Spain

City of Hope National Medical Center Duarte California USA

Clalit National Cancer Control Center Haifa Israel

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA

Clinical Epidemiology Unit Faculty of Medicine Memorial University of Newfoundland St John's Newfoundland Canada

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA

Clinical Research Division Fred Hutchinson Cancer Research Center Seattle Washington USA

Colorectal Oncogenomics Group Genetic Epidemiology Laboratory Department of Clinical Pathology The University of Melbourne Melbourne Victoria Australia

Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor Michigan USA

Department of Biostatistics University of Washington Seattle Washington USA

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center The Ohio State University Columbus Ohio USA

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Computer Science Stanford University Stanford California USA

Department of Epidemiology and Biostatistics Imperial College London London UK

Department of Epidemiology German Institute of Human Nutrition Potsdam Rehbrücke Germany

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston Massachusetts USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Johns Hopkins University Baltimore Maryland USA

Department of Epidemiology School of Public Health and Institute of Health and Environment Seoul National University Seoul South Korea

Department of Epidemiology University of Washington Seattle Washington USA

Department of Family Medicine University of Virginia Charlottesville Virginia USA

Department of General Surgery University Hospital Rostock Rostock Germany

Department of Genetics and Genome Sciences Case Western Reserve University School of Medicine Case Comprehensive Cancer Center Cleveland Ohio USA

Department of Genetics Stanford University Stanford California USA

Department of Genome Sciences University of Washington Seattle Washington USA

Department of Health Science Research Mayo Clinic Scottsdale Arizona USA

Department of Human Genetics Graduate School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA

Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston Massachusetts USA

Department of Internal Medicine University of Utah Health Salt Lake City Utah USA

Department of Medicine 1 University Hospital Dresden Technische Universität Dresden Dresden Germany

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh Pennsylvania USA

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles California USA

Department of Medicine University of North Carolina School of Medicine Chapel Hill North Carolina USA

Department of Medicine University of Washington School of Medicine Seattle Washington USA

Department of Medicine Weill Cornell Medical College New York New York USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Nutrition Harvard T H Chan School of Public Health Harvard University Boston Massachusetts USA

Department of Oncologic Pathology Dana Farber Cancer Institute Boston Massachusetts USA

Department of Pathology School of Medicine Umm Al Qura'a University Mecca Saudi Arabia

Department of Population and Quantitative Health Sciences Case Western Reserve University 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 Preventive Medicine Keck School of Medicine of the University of Southern California Los Angeles California USA

Department of Preventive Medicine USC Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine Los Angeles California USA

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Public Health Sciences School of Medicine University of California Davis Davis California USA

Department of Public Health Solutions National Institute for Health and Welfare Helsinki Finland

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Departments of Cancer Biology and Genetics and Internal Medicine The Ohio State University Columbus Ohio USA

Departments of Medicine and Genetics Case Comprehensive Cancer Center Case Western Reserve University and University Hospitals of Cleveland Cleveland Ohio USA

Dipartimento di Medicina Clinica e Chirurgia University of Naples Federico 2 Naples Italy

Discipline of Genetics Memorial University of Newfoundland St John's Newfoundland Canada

Division of Cancer Control and Population Sciences National Cancer Institute Bethesda Maryland USA

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland USA

Division of Cancer Epidemiology German Cancer Research Centre Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Centre Heidelberg Germany

Division of Clinical Epidemiology German Cancer Research Centre Heidelberg Germany

Division of Epidemiology and Community Health University of Minnesota Minneapolis Minnesota USA

Division of Epidemiology Department of Population Health New York University School of Medicine New York New York USA

Division of Epidemiology Vanderbilt Epidemiology Center Vanderbilt University School of Medicine Nashville Tennessee USA

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts USA

Division of Human Genetics Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus Ohio USA

Division of Human Nutrition and Health Wageningen University and Research Wageningen The Netherlands

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology MayoClinic Rochester Minnesota USA

Division of Preventive Oncology German Cancer Research Centre Heidelberg Germany

Division of Research Kaiser Permanente Medical Care Program Oakland California USA

Division of Research Kaiser Permanente Northern California Oakland California USA

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Gastroenterology Department Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Spain

Genomic Medicine and Family Cancer Clinic Royal Melbourne Hospital Melbourne Victoria Australia

Genomic Medicine Institute Cleveland Clinic Cleveland Ohio USA

German Cancer Consortium Heidelberg Germany

Hellenic Health Foundation Athens Greece

Huntsman Cancer Institute and Department of Population Health Sciences University of Utah Health Salt Lake City Utah USA

Institut Gustave Roussy Université Paris Saclay Villejuif France

Institute for Health Research Kaiser Permanente Colorado Denver Colorado USA

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Cancer Research Department of Medicine 1 Medical University of Vienna Vienna Austria

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Epidemiology PopGen Biobank Christian Albrechts University Kiel Kiel Germany

Laboratoire de Mathématiques Appliquées MAP5 Université Paris Descartes Paris France

Leeds Institute of Medical Research at St James's University of Leeds Leeds UK

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada

Medical Faculty University of Heidelberg Heidelberg Germany

Nutrition and Metabolism Section International Agency for Research on Cancer World Health Organization Lyon France

Ontario Institute for Cancer Research Toronto Ontario Canada

Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

Public Health Division of Gipuzkoa Health Department of Basque Country San Sebastian Spain

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington USA

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

School of Public Health Imperial College London London UK

Service de Génétique Médicale Centre Hospitalier Universitaire de Nantes Nantes France

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington USA

The Clalit Health Services Personalized Genomic Service Carmel Medical Center Haifa Israel

Translational Genomics Research Institute An Affiliate of City of Hope Phoenix Arizona USA

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain

University of Hawai'i Cancer Center Honolulu Hawaii USA

UPMC Hillman Cancer Center Pittsburgh Pennsylvania USA

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

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Commentary: Special Issue: Current Understanding of Colorectal and Pancreatic Cancers

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation

The dynamics of telomere length in primary and metastatic colorectal cancer lesions

Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis