. 2020 Sep 3;107(3):432-444.

doi: 10.1016/j.ajhg.2020.07.006. Epub 2020 Aug 5.

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

Minta Thomas¹, Lori C Sakoda², Michael Hoffmeister³, Elisabeth A Rosenthal⁴, Jeffrey K Lee⁵, Franzel J B van Duijnhoven⁶, Elizabeth A Platz⁷, Anna H Wu⁸, Christopher H Dampier⁹, Albert de la Chapelle¹⁰, Alicja Wolk¹¹, Amit D Joshi¹², Andrea Burnett-Hartman¹³, Andrea Gsur¹⁴, Annika Lindblom¹⁵, Antoni Castells¹⁶, Aung Ko Win¹⁷, Bahram Namjou¹⁸, Bethany Van Guelpen¹⁹, Catherine M Tangen²⁰, Qianchuan He¹, Christopher I Li¹, Clemens Schafmayer²¹, Corinne E Joshu⁷, Cornelia M Ulrich²², D Timothy Bishop²³, Daniel D Buchanan²⁴, Daniel Schaid²⁵, David A Drew²⁶, David C Muller²⁷, David Duggan²⁸, David R Crosslin²⁹, Demetrius Albanes³⁰, Edward L Giovannucci³¹, Eric Larson³², Flora Qu¹, Frank Mentch³³, Graham G Giles³⁴, Hakon Hakonarson³³, Heather Hampel³⁵, Ian B Stanaway⁴, Jane C Figueiredo³⁶, Jeroen R Huyghe¹, Jessica Minnier³⁷, Jenny Chang-Claude³⁸, Jochen Hampe³⁹, John B Harley¹⁸, Kala Visvanathan⁷, Keith R Curtis¹, Kenneth Offit⁴⁰, Li Li⁴¹, Loic Le Marchand⁴², Ludmila Vodickova⁴³, Marc J Gunter⁴⁴, Mark A Jenkins¹⁷, Martha L Slattery⁴⁵, Mathieu Lemire⁴⁶, Michael O Woods⁴⁷, Mingyang Song⁴⁸, Neil Murphy⁴⁴, Noralane M Lindor⁴⁹, Ozan Dikilitas⁵⁰, Paul D P Pharoah⁵¹, Peter T Campbell⁵², Polly A Newcomb⁵³, Roger L Milne³⁴, Robert J MacInnis⁵⁴, Sergi Castellví-Bel¹⁶, Shuji Ogino⁵⁵, Sonja I Berndt³⁰, Stéphane Bézieau⁵⁶, Stephen N Thibodeau⁵⁷, Steven J Gallinger⁵⁸, Syed H Zaidi⁵⁹, Tabitha A Harrison¹, Temitope O Keku⁶⁰, Thomas J Hudson⁵⁹, Veronika Vymetalkova⁴³, Victor Moreno⁶¹, Vicente Martín⁶², Volker Arndt³, Wei-Qi Wei⁶³, Wendy Chung⁶⁴, Yu-Ru Su¹, Richard B Hayes⁶⁵, Emily White⁶⁶, Pavel Vodicka⁴³, Graham Casey⁶⁷, Stephen B Gruber⁶⁸, Robert E Schoen⁶⁹, Andrew T Chan⁷⁰, John D Potter⁷¹, Hermann Brenner⁷², Gail P Jarvik⁷³, Douglas A Corley⁵, Ulrike Peters⁷⁴, Li Hsu⁷⁵

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
³ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁴ Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA.
⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
⁶ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen 176700, the Netherlands.
⁷ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
⁸ University of Southern California, Preventative Medicine, Los Angeles, CA 90089, USA.
⁹ Department of Surgery, University of Virginia Health System, Charlottesville, VA 22903, USA.
¹⁰ Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
¹¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
¹² Clinical 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.
¹³ Institute for Health Research, Kaiser Permanente Colorado, Denver, CO 80014, USA.
¹⁴ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna 1090, Austria.
¹⁵ Department of Clinical Genetics, Karolinska University Hospital, Stockholm 17177, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden.
¹⁶ Gastroenterology 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.
¹⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia.
¹⁸ Center 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.
¹⁹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå 90187, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå 90187, Sweden.
²⁰ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²¹ Department of General Surgery, University Hospital Rostock, Rostock 18051, Germany.
²² Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA.
²³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS2 9JT, UK.
²⁴ University 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.
²⁵ Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
²⁶ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
²⁷ School of Public Health, Imperial College London, London SW7 2AZ, UK.
²⁸ Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ 85003, USA.
²⁹ Department of Bioinformatics and Medical Education, University of Washington Medical Center, Seattle, WA 98195, USA.
³⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
³¹ 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; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02108, USA.
³² Kaiser Permanente Washington Research Institute, Seattle, WA 98101, USA.
³³ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³⁴ Centre 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.
³⁵ Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
³⁶ Department 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.
³⁷ School of Public Health, Oregon Health & Science University, Portland, OR 97239, USA.
³⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120 Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg 20246, Germany.
³⁹ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden 01062, Germany.
⁴⁰ Clinical 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.
⁴¹ Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA.
⁴² University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁴³ Department 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.
⁴⁴ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon 69372, France.
⁴⁵ Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA.
⁴⁶ PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
⁴⁷ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL A1B 3R7, Canada.
⁴⁸ Clinical 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.
⁴⁹ Department of Health Science Research, Mayo Clinic, Scottsdale, AZ 85260, USA.
⁵⁰ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
⁵¹ Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, UK.
⁵² Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA 30303, USA.
⁵³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Washington, Seattle, WA 98195, USA.
⁵⁴ Centre 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.
⁵⁵ Department 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.
⁵⁶ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes 44093, France.
⁵⁷ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 85054, USA.
⁵⁸ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G1X5, Canada.
⁵⁹ Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
⁶⁰ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶¹ Oncology 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.
⁶² CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain; Biomedicine Institute (IBIOMED), University of León, León 24071, Spain.
⁶³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁶⁴ Office 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.
⁶⁵ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY 10016, USA.
⁶⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁶⁷ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
⁶⁸ Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁶⁹ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA.
⁷⁰ Clinical 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.
⁷¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.
⁷² Division 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.
⁷³ Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA; Genome Sciences, University of Washington Medical Center, Seattle, WA 98195, USA.
⁷⁴ Public 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.
⁷⁵ Public 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.

PMID: 32758450
PMCID: PMC7477007
DOI: 10.1016/j.ajhg.2020.07.006

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

Minta Thomas et al. Am J Hum Genet. 2020.

. 2020 Sep 3;107(3):432-444.

doi: 10.1016/j.ajhg.2020.07.006. Epub 2020 Aug 5.

Authors

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
³ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
⁴ Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA.
⁵ Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA.
⁶ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen 176700, the Netherlands.
⁷ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
⁸ University of Southern California, Preventative Medicine, Los Angeles, CA 90089, USA.
⁹ Department of Surgery, University of Virginia Health System, Charlottesville, VA 22903, USA.
¹⁰ Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
¹¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
¹² Clinical 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.
¹³ Institute for Health Research, Kaiser Permanente Colorado, Denver, CO 80014, USA.
¹⁴ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna 1090, Austria.
¹⁵ Department of Clinical Genetics, Karolinska University Hospital, Stockholm 17177, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden.
¹⁶ Gastroenterology 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.
¹⁷ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3000, Australia.
¹⁸ Center 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.
¹⁹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå 90187, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå 90187, Sweden.
²⁰ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
²¹ Department of General Surgery, University Hospital Rostock, Rostock 18051, Germany.
²² Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA.
²³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS2 9JT, UK.
²⁴ University 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.
²⁵ Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
²⁶ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
²⁷ School of Public Health, Imperial College London, London SW7 2AZ, UK.
²⁸ Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ 85003, USA.
²⁹ Department of Bioinformatics and Medical Education, University of Washington Medical Center, Seattle, WA 98195, USA.
³⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
³¹ 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; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02108, USA.
³² Kaiser Permanente Washington Research Institute, Seattle, WA 98101, USA.
³³ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³⁴ Centre 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.
³⁵ Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
³⁶ Department 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.
³⁷ School of Public Health, Oregon Health & Science University, Portland, OR 97239, USA.
³⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120 Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg 20246, Germany.
³⁹ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden 01062, Germany.
⁴⁰ Clinical 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.
⁴¹ Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA.
⁴² University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁴³ Department 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.
⁴⁴ Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon 69372, France.
⁴⁵ Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA.
⁴⁶ PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
⁴⁷ Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL A1B 3R7, Canada.
⁴⁸ Clinical 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.
⁴⁹ Department of Health Science Research, Mayo Clinic, Scottsdale, AZ 85260, USA.
⁵⁰ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
⁵¹ Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, UK.
⁵² Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA 30303, USA.
⁵³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Washington, Seattle, WA 98195, USA.
⁵⁴ Centre 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.
⁵⁵ Department 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.
⁵⁶ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes 44093, France.
⁵⁷ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 85054, USA.
⁵⁸ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G1X5, Canada.
⁵⁹ Ontario Institute for Cancer Research, Toronto, ON M5G0A3, Canada.
⁶⁰ Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶¹ Oncology 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.
⁶² CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain; Biomedicine Institute (IBIOMED), University of León, León 24071, Spain.
⁶³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁶⁴ Office 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.
⁶⁵ Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY 10016, USA.
⁶⁶ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁶⁷ Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
⁶⁸ Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁶⁹ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15219, USA.
⁷⁰ Clinical 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.
⁷¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.
⁷² Division 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.
⁷³ Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA 98195, USA; Genome Sciences, University of Washington Medical Center, Seattle, WA 98195, USA.
⁷⁴ Public 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.
⁷⁵ Public 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.

PMID: 32758450
PMCID: PMC7477007
DOI: 10.1016/j.ajhg.2020.07.006

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.

Keywords: cancer risk prediction; colorectal cancer; machine learning; polygenic risk score.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Description of Three Approaches to Derive Polygenic Risk Scores (PRS) for Colorectal Cancer

**Figure 2**
Disease Probabilities for Developing CRC and Advanced Adenoma Probabilities of developing CRC (left) and advanced neoplasia (right) by age for PRS in the top 5% and bottom 5%, based on models derived from three approaches: known GWAS variants (Approach 1), SNP selection + machine learning with ridge regression (Approach 2), and LDpred with ρ = 0.003 (Approach 3). Average is the overall age-specific CRC (left) and advanced neoplasia (right) probabilities for the GERA.

**Figure 3**
Disease Probabilities and Proportion of Cases (95% CI) Subjects Stratified by the Deciles of LDpred-Derived PRS

See this image and copyright information in PMC

Comment in

Age dependency of the polygenic risk score for colorectal cancer.
Li S, Hopper JL. Li S, et al. Am J Hum Genet. 2021 Mar 4;108(3):525-526. doi: 10.1016/j.ajhg.2021.02.002. Am J Hum Genet. 2021. PMID: 33667395 Free PMC article. No abstract available.
Response to Li and Hopper.
Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Win AK, Namjou B, Van Guelpen B, Tangen CM, He Q, Li CI, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellví-Bel S, Ogino S, Berndt SI, Bézieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martín V, Arndt V, Wei WQ, Chung W, Su YR, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, Hsu L. Thomas M, et al. Am J Hum Genet. 2021 Mar 4;108(3):527-529. doi: 10.1016/j.ajhg.2021.02.003. Am J Hum Genet. 2021. PMID: 33667396 Free PMC article. No abstract available.

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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

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