BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia

Biomedical Center Faculty of Medicine Pilsen Charles University Prague Czech Republic

Biostatistics Unit Kaiser Permanente Washington Health Research Institute Seattle Washington

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

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

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

Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville Victoria Australia

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center and Technion Israel Institute of Technology 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 Hanover New Hampshire

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

Department of Epidemiology University of Michigan Ann Arbor Michigan

Department of Family Medicine University of Virginia Charlottesville Virginia

Department of Gastroenterology Kaiser Permanente San Francisco Medical Center San Francisco California

Department of Health Systems Science Kaiser Permanente Bernard J Tyson School of Medicine Pasadena California

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

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

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles California

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

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

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

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 Population Health New York University School of Medicine New York New York

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School 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 Research Kaiser Permanente Northern California Oakland California

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

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 Institutet Stockholm Sweden

Leeds Institute of Cancer and Pathology University of Leeds Leeds United Kingdom

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

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

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

Oncology Data Analytics Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

University of Hawaii Cancer Center Honolulu Hawaii

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

VA Cooperative Studies Program Epidemiology Center Durham Veterans Affairs Health Care System Durham North Carolina

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

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