Recent studies have demonstrated that for various diseases, incorporating polygenic risk scores (PRSs) for other traits and diseases into the PRS-based risk prediction model may improve predictive performance - known as Multiple Polygenic Score (MPS) approach. We aimed to examine whether the MPS approach improves colorectal cancer (CRC) risk prediction. We included 2,187 non-CRC PRSs from the polygenic Score (PGS) Catalog and used machine learning (ML) models to select the most predictive non-CRC PRSs, utilizing individual-level data from 31,257 CRC cases and 33,408 controls. An independent dataset from the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (4,852 cases and 67,939 controls) was randomly split into subsets for model estimation and validation. The model combined MPS with two existing CRC-PRSs based on known loci and genome-wide genotyping. We then assessed model performance by calculating the area under the receiver operating curve (AUC) in the validation set and performed 1,000 bootstrapped iterations to evaluate AUC improvements. The ML model selected 337 non-CRC PRSs predictive of CRC risk. Adding MPS to the CRC-PRSs significantly improved AUC by 0.017 (95% CI: 0.011-0.022, p < 0.0001) when combined with known-loci CRC-PRS, 0.005 (95% CI: 0.002-0.007, p = 0.0005) with genome-wide CRC-PRS, and 0.004 (95% CI: 0.002-0.006, p = 0.0005) with both the known loci and genome-wide CRC-PRSs. These findings demonstrate MPS's potential to refine CRC risk prediction models and highlight opportunities for further advancements in risk prediction.

Broad Institute of Harvard and MIT Cambridge MA USA

Cancer Epidemiology and Prevention Research Unit School of Public Health Imperial College London London UK

Center for Cancer Research Medical University of Vienna Vienna Austria

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

Center for Genetic Epidemiology Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles CA USA

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

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

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

Colorado Center for Personalized Medicine University of Colorado Anschutz Medical Campus Aurora CO USA

Consortium for Biomedical Research in Epidemiology and Public Health Madrid 28029 Spain

Department of Biostatistics University of Washington Seattle WA USA

Department of Clinical Sciences Faculty of Medicine and health Sciences Universitat de Barcelona Institute of Complex Systems L'Hospitalet de Llobregat Barcelona 08908 Spain

Department of Diagnostics and Intervention Oncology Unit Umeå University Umeå Sweden

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

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Epidemiology University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Gastroenterology Kaiser Permanente San Francisco Medical Center San Francisco CA USA

Department of Genome Sciences University of Washington School of Medicine Seattle WA USA

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

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

Department of Medicine Division of Medical Genetics University of Washington Seattle WA USA

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

Department of Population Science American Cancer Society Atlanta Georgia

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

Departments of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA USA

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

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD USA

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

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

Division of Gastroenterology University of California San Francisco San Francisco CA USA

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

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

Gastroenterology Department Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas University of Barcelona Barcelona Spain

German Cancer Consortium Heidelberg Germany

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

Institute of Science Tokyo Tokyo Japan

Intermountain Health Salt Lake City UT USA

Kaiser Permanente Division of Research Oakland CA USA

Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

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

ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona 08908 Spain

Oncology Data Analytics Program L'Hospitalet del Llobregat Barcelona 08908 Spain

Princess Margaret Cancer Centre University Health Network Toronto Canada

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

Public Health Sciences Division Fred Hutchinson Cancer Center Seattle WA USA

School of Public Health University of Washington Seattle WA USA

Service de Génétique médicale Nantes Université CHU de Nantes Nantes F 44000 France

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD USA

Slone Epidemiology Center at Boston University Boston MA USA

University of Hawaii Cancer Center Honolulu HI USA

University of Washington Seattle WA USA

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

Zobrazit více v PubMed

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