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Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

About this Publication
Title
Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.
Pubmed ID
31866242 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Gastroenterology. 2019 Dec 19
Authors
Archambault AN, Su YR, Jeon J, Thomas M, Lin Y, Conti DV, Win AK, Sakoda LC, Lansdorp-Vogelaar I, Peterse EFP, Zauber AG, Duggan D, Holowatyj AN, Huyghe JR, Brenner H, Cotterchio M, Bézieau S, Schmit SL, Edlund CK, Southey MC, ...show more MacInnis RJ, Campbell PT, Chang-Claude J, Slattery ML, Chan AT, Joshi AD, Song M, Cao Y, Woods MO, White E, Weinstein SJ, Ulrich CM, Hoffmeister M, Bien SA, Harrison TA, Hampe J, Li CI, Schafmayer C, Offit K, Pharoah PD, Moreno V, Lindblom A, Wolk A, Wu AH, Li L, Gunter MJ, Gsur A, Keku TO, Pearlman R, Bishop DT, Castellví-Bel S, Moreira L, Vodicka P, Kampman E, Giles GG, Albanes D, Baron JA, Berndt SI, Brezina S, Buch S, Buchanan DD, Trichopoulou A, Severi G, Chirlaque MD, Sánchez MJ, Palli D, Kühn T, Murphy N, Cross AJ, Burnett-Hartman AN, Chanock SJ, de la Chapelle A, Easton DF, Elliott F, English DR, Feskens EJM, FitzGerald LM, Goodman PJ, Hopper JL, Hudson TJ, Hunter DJ, Jacobs EJ, Joshu CE, Küry S, Markowitz SD, Milne RL, Platz EA, Rennert G, Rennert HS, Schumacher FR, Sandler RS, Seminara D, Tangen CM, Thibodeau SN, Toland AE, van Duijnhoven FJB, Visvanathan K, Vodickova L, Potter JD, Männistö S, Weigl K, Figueiredo J, Martín V, Larsson SC, Parfrey PS, Huang WY, Lenz HJ, Castelao JE, Gago-Dominguez M, Muñoz-Garzón V, Mancao C, Haiman CA, Wilkens LR, Siegel E, Barry E, Younghusband B, Van Guelpen B, Harlid S, Zeleniuch-Jacquotte A, Liang PS, Du M, Casey G, Lindor NM, Le Marchand L, Gallinger SJ, Jenkins MA, Newcomb PA, Gruber SB, Schoen RE, Hampel H, Corley DA, Hsu L, Peters U, Hayes RB
Affiliations
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Department of Epidemiology, University of Michigan, Ann Arbor, Michigan.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Research, Kaiser Permanente Northern California, Oakland, California.
  • Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
  • Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Translational Genomics Research Institute, An Affiliate of City of Hope, Phoenix, Arizona.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
...show more
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Population Health and Prevention, Cancer Care Ontario, Toronto, Ontario, Canada.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
  • 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.
  • Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, 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.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
  • Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
  • 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.
  • 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.
  • Department of Nutrition, 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.
  • Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
  • Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 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 Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
  • Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.
  • Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
  • Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
  • 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, Spain.
  • 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, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
  • Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
  • 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.
  • Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.
  • Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • 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.
  • Hellenic Health Foundation, Athens, Greece.
  • Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Médecine, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
  • CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain.
  • Escuela Andaluza de Salud Pública, CIBER de Epidemiología y Salud Pública, Granada, Spain.
  • Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
  • School of Public Health, Imperial College London, London, UK.
  • Institute for Health Research, Kaiser Permanente Colorado, Aurora, Colorado.
  • Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
  • Department of Medicine, Weill Cornell Medical College, New York, New York.
  • Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • 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.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 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.
  • Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • 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 Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio.
  • Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
  • Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty, University of Heidelberg, Heidelberg, Germany.
  • 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.
  • CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Biomedicine Institute (IBIOMED), University of León, León, Spain.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • The Clinical Epidemiology Unit, Memorial University Medical School, St. John's, Newfoundland, Canada.
  • Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
  • Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Oncology and Genetics Unit, Vigo, Spain.
  • Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain; Moores Cancer Center, University of California San Diego, La Jolla, California.
  • Radiotherapy Department, Complejo Hospitalario Universitario de Vigo, SERGAS, Vigo, Spain.
  • Genentech, Inc., Basel, Switzerland.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
  • Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
  • Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden; Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Department of Medicine, New York University School of Medicine, New York, New York.
  • Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
  • Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Public Health, University of Washington, Seattle, Washington.
  • Center for Precision Medicine & Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • Division of Research, Kaiser Permanente Northern California, Oakland, California.
  • 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; Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada. Electronic address: upeters@fredhutch.org.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, New York. Electronic address: richard.b.hayes@nyulangone.org.
Abstract

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=5.61x10-5). 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 preventative measures.

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