BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia

Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Victoria Australia; Menzies Institute for Medical Research University of Tasmania Hobart Tasmania Australia

Cancer Prevention and Control Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain; CIBER in Epidemiology and Public Health Madrid Spain; Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Cancer Risk Factors and Life Style Epidemiology Unit Institute for Cancer Research Prevention and Clinical Network ISPRO Florence Italy

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

Center for Precision Medicine and Department of Medical Oncology and Therapeutics Research City of Hope National Medical Center Duarte California

Center for Public Health Genomics University of Virginia Charlottesville Virginia

Centre de Recherche en Épidémiologie et Santé des Populations Facultés de Médecine Université Paris Saclay Gustave Roussy Villejuif France

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

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia; Cancer Epidemiology and Intelligence 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; Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville Victoria Australia; Genomic Medicine and Family Cancer Clinic The Royal Melbourne Hospital Parkville Victoria Australia; University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Parkville Victoria Australia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia; Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa Florida

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia; Department of Epidemiology School of Public Health and Institute of Health and Environment Seoul National University Seoul South Korea

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

CIBER in Epidemiology and Public Health University of León León Spain

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

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Division of Public Health Sciences Department of Surgery Washington University in St Louis St Louis Missouri

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

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

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa Florida

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden; Department of Molecular Medicine and Surgery Karolinska Institutet 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; Clalit National Cancer Control Center Haifa Israel

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York

Department of Epidemiology Geisel School of Medicine at Dartmouth Lebanon New Hampshire

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston Massachusetts; Nuffield Department of Population Health University of Oxford Oxford UK

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

Department of Epidemiology University of Michigan Ann Arbor Michigan

Department of Epidemiology University of Washington School of Public Health Seattle Washington

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 Health Science Research Mayo Clinic Scottsdale Arizona

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 New York University School of Medicine New York New York

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

Department of Medicine Weill Cornell Medical College New York New York

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 Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

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

Department of Population and Quantitative Health Sciences Case Western Reserve University Cleveland Ohio

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

Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles California; Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa Florida

Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles California; Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles California

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

Department of Public Health Erasmus MC University Medical Center Rotterdam The Netherlands

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

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

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

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

Division of Cancer Epidemiology German Cancer Research Center Hamburg Germany

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 Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany; Medical Faculty University of Heidelberg Heidelberg Germany

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

Division of Gastroenterology 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; Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts; Broad Institute of Harvard and MIT Cambridge Massachusetts; Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston Massachusetts; Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University 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

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Division of Medical Oncology Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles California

Division of Research Kaiser Permanente Northern California Oakland California

Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii

Escuela Andaluza de Salud Pública CIBER de Epidemiología y Salud Pública Granada Spain

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

Genentech Inc Basel Switzerland

Genetic Epidemiology Laboratory Department of Pathology The University of Melbourne Melbourne Australia

Genomic Medicine Group Galician Foundation of Genomic Medicine Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain; Moores Cancer Center University of California San Diego La Jolla California

Hellenic Health Foundation Athens Greece

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

Institute for Health Research Kaiser Permanente Colorado Aurora Colorado

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

Institute of Environmental Medicine Karolinska Institute Stockholm Sweden

Instituto de Investigación Sanitaria Galicia Sur Xerencia de Xestion Integrada de Vigo SERGAS Oncology and Genetics Unit Vigo Spain

Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

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

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

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

Ontario Institute for Cancer Research Toronto Ontario Canada

Population Health and Prevention Cancer Care Ontario Toronto Ontario Canada

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

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 School of Public Health 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; Memorial University of Newfoundland Discipline of Genetics St John's Newfoundland Canada

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

Radiotherapy Department Complejo Hospitalario Universitario de Vigo SERGAS Vigo Spain

School of Public Health Imperial College London London UK

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

The Clinical Epidemiology Unit Memorial University Medical School St John's Newfoundland Canada

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

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

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Gastroenterology. 2021 May;160(6):2214-2215. doi: 10.1053/j.gastro.2020.09.064. PubMed

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

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer

Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort

Cancer Predisposition Genes in Cancer-Free Families

Colorectal Adenomas-Genetics and Searching for New Molecular Screening Biomarkers