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    American journal of human genetics. 2020 Jul 29. pii: S0002-9297(20)30236-6. doi: 10.1016/j.ajhg.2020.07.006
    Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
    Thomas M1,  Sakoda LC2,  Hoffmeister M3,  Rosenthal EA4,  Lee JK5,  van Duijnhoven FJB6,  Platz EA7,  Wu AH8,  Dampier CH9,  de la Chapelle A10,  Wolk A11,  Joshi AD12,  Burnett-Hartman A13,  Gsur A14,  Lindblom A15,  Castells A16,  Win AK17,  Namjou B18,  Van Guelpen B19,  Tangen CM20,  He Q21,  Li CI22,  Schafmayer C23,  Joshu CE24,  Ulrich CM25,  Bishop DT26,  Buchanan DD27,  Schaid D28,  Drew DA29,  Muller DC30,  Duggan D31,  Crosslin DR32,  Albanes D33,  Giovannucci EL34,  Larson E35,  Qu F36,  Mentch F37,  Giles GG38,  Hakonarson H39,  Hampel H40,  Stanaway IB41,  Figueiredo JC42,  Huyghe JR43,  Minnier J44,  Chang-Claude J45,  Hampe J46,  Harley JB47,  Visvanathan K48,  Curtis KR49,  Offit K50,  Li L51,  Le Marchand L52,  Vodickova L53,  Gunter MJ54,  Jenkins MA55,  Slattery ML56,  Lemire M57,  Woods MO58,  Song M59,  Murphy N60,  Lindor NM61,  Dikilitas O62,  Pharoah PDP63,  Campbell PT64,  Newcomb PA65,  Milne RL66,  MacInnis RJ67,  Castellví-Bel S68,  Ogino S69,  Berndt SI70,  Bézieau S71,  Thibodeau SN72,  Gallinger SJ73,  Zaidi SH74,  Harrison TA75,  Keku TO76,  Hudson TJ77,  Vymetalkova V78,  Moreno V79,  Martín V80,  Arndt V81,  Wei WQ82,  Chung W83,  Su YR84,  Hayes RB85,  White E86,  Vodicka P87,  Casey G88,  Gruber SB89,  Schoen RE90,  Chan AT91,  Potter JD92,  Brenner H93,  Jarvik GP94,  Corley DA95,  Peters U96,  Hsu L97
    Author information
    1Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    2Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
    3Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    4Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA.
    5Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
    6Division of Human Nutrition and Health, Wageningen University & Research, Wageningen 176700, the Netherlands.
    7Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
    8University of Southern California, Preventative Medicine, Los Angeles, CA 90089, USA.
    9Department of Surgery, University of Virginia Health System, Charlottesville, VA 22903, USA.
    10Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
    11Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
    12Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
    13Institute for Health Research, Kaiser Permanente Colorado, Denver, CO 80014, USA.
    14Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna 1090, Austria.
    15Department of Clinical Genetics, Karolinska University Hospital, Stockholm 17177, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden.
    16Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona 08007, Spain.
    17Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia.
    18Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Cincinnati VA Medical Center, Cincinnati, OH 45229, USA.
    19Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå 90187, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå 90187, Sweden.
    20SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    21Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    22Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    23Department of General Surgery, University Hospital Rostock, Rostock 18051, Germany.
    24Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
    25Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA.
    26Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS2 9JT, UK.
    27University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC 3010, Australia; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC 3010, Australia.
    28Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
    29Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
    30School of Public Health, Imperial College London, London SW7 2AZ, UK.
    31Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ 85003, USA.
    32Department of Bioinformatics and Medical Education, University of Washington Medical Center, Seattle, WA 98195, USA.
    33Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    34Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02108, USA.
    35Kaiser Permanente Washington Research Institute, Seattle, WA 98101, USA.
    36Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    37Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
    38Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia; Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
    39Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
    40Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
    41Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA.
    42Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
    43Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    44School of Public Health, Oregon Health & Science University, Portland, OR 97239, USA.
    45Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120 Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg 20246, Germany.
    46Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden 01062, Germany.
    47Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Cincinnati VA Medical Center, Cincinnati, OH 45229, USA.
    48Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
    49Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    50Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College, NY 10065, USA.
    51Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA.
    52University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
    53Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
    54Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon 69372, France.
    55Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia.
    56Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA.
    57PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
    58Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL A1B 3R7, Canada.
    59Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA.
    60Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon 69372, France.
    61Department of Health Science Research, Mayo Clinic, Scottsdale, AZ 85260, USA.
    62Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
    63Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, UK.
    64Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA 30303, USA.
    65Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Washington, Seattle, WA 98195, USA.
    66Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia; Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
    67Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia; Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia.
    68Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona 08007, Spain.
    69Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
    70Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
    71Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes 44093, France.
    72Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 85054, USA.
    73Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G1X5, Canada.
    74Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
    75Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    76Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599, USA.
    77Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
    78Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
    79Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona 08908, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona 08907, Spain; ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
    80CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain; Biomedicine Institute (IBIOMED), University of León, León 24071, Spain.
    81Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    82Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
    83Office of Research & Development, Department of Veterans Affairs, Washington, DC 20420, USA; Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
    84Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    85Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY 10016, USA.
    86Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
    87Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, 323 00 Pilsen, Czech Republic.
    88Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
    89Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
    90Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA.
    91Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA.
    92Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.
    93Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    94Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA; Genome Sciences, University of Washington Medical Center, Seattle, WA 98195, USA.
    95Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
    96Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA. Electronic address: upeters@fredhutch.org.
    97Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA. Electronic address: lih@fredhutch.org.
    Abstract

    Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.


    Copyright © 2020 American Society of Human Genetics. All rights reserved.

    KEYWORDS: cancer risk prediction, colorectal cancer, machine learning, polygenic risk score

    Publikations ID: 32758450
    Quelle: öffnen
     
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