BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia; Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia; Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia; Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

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

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

Center for Public Health Genomics University of Virginia Charlottesville Virginia

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

CESP Université Paris Descartes France

CIBER in Epidemiology and Public Health University of León León Spain

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York; Department of Medicine Weill Cornell Medical College New York New York

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Madrid Spain; Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville Victoria 3010 Australia; University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Parkville Victoria 3010 Australia; Genetic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville Victoria Australia

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

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden; Department of Molecular Medicine and Surgery Karolinska Institute Stockholm Sweden

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel; Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston Massachusetts; Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts; Cancer Immunology and Cancer Epidemiology Programs Dana Farber Harvard Cancer Center Boston Massachusetts; Broad Institute of MIT and Harvard Cambridge Massachusetts

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

Department of Epidemiology Regional Health Council IMIB Arrixaca Murcia University Murcia Spain; CIBER in Epidemiology and Public Health Madrid Spain

Department of Family Medicine University of Virginia Charlottesville Virginia

Department of General and Thoracic Surgery University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece; Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

Department of Internal Medicine University of Utah Salt Lake City Utah

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

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

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

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic; Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

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

Department of Preventive Medicine Chonnam National University Medical School Gwangju Korea; Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun Korea

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden; Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda Maryland

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

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

Division of Epidemiology Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University School of Medicine Nashville Tennessee

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston Massachusetts; Department of Nutrition Harvard T H Chan School of Public Health Boston Massachusetts

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

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

Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

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

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

Institute for Health Research Kaiser Permanente Colorado Denver Colorado

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

Institute of Environmental Medicine Karolinska Institute Stockholm Sweden

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

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht The Netherlands

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

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

MRC Integrative Epidemiology Unit Bristol Biomedical Research Centre University Hospitals Bristol NHS Foundation Trust and the University of Bristol Bristol UK

National Institute for Health Innovation School of Population Health The University of Auckland Auckland New Zealand

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington; Centre for Public Health Research Massey University Wellington New Zealand

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington; Department of Biostatistics University of Washington Seattle Washington

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington; Department of Epidemiology University of Washington Seattle Washington

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington; Division of Research Kaiser Permanente Northern California Oakland California

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington; School of Public Health University of Washington Seattle Washington

Section of Nutrition and Metabolism International Agency for Research on Cancer Lyon France

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington

University of Hawaii Cancer Center Honolulu Hawaii

University of Southern California Preventive Medicine Los Angeles California

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Non-Genomic Hallmarks of Aging-The Review

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study