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Nat Genet. 2018 Dec 3. doi: 10.1038/s41588-018-0286-6. [Epub ahead of print]

Discovery of common and rare genetic risk variants for colorectal cancer.

Huyghe JR1, Bien SA1, Harrison TA1, Kang HM2, Chen S2, Schmit SL3, Conti DV4, Qu C1, Jeon J5, Edlund CK4, Greenside P6, Wainberg M7, Schumacher FR8, Smith JD9, Levine DM10, Nelson SC10, Sinnott-Armstrong NA11, Albanes D12, Alonso MH13,14,15, Anderson K16, Arnau-Collell C17, Arndt V18, Bamia C19,20, Banbury BL1, Baron JA21, Berndt SI12, Bézieau S22, Bishop DT23, Boehm J24, Boeing H25, Brenner H18,26,27, Brezina S28, Buch S29, Buchanan DD30,31,32, Burnett-Hartman A33, Butterbach K18, Caan BJ34, Campbell PT35, Carlson CS1,36, Castellví-Bel S17, Chan AT37,38,39,40,41,42, Chang-Claude J43,44, Chanock SJ12, Chirlaque MD14,45, Cho SH46, Connolly CM1, Cross AJ47,48, Cuk K18, Curtis KR1, de la Chapelle A49, Doheny KF50, Duggan D51, Easton DF52,53, Elias SG54, Elliott F23, English DR55,56, Feskens EJM57, Figueiredo JC58,59, Fischer R60, FitzGerald LM56,61, Forman D62, Gala M37,39, Gallinger S63, Gauderman WJ4, Giles GG55,56, Gillanders E64, Gong J1, Goodman PJ65, Grady WM66, Grove JS67, Gsur A28, Gunter MJ68, Haile RW69, Hampe J29, Hampel H70, Harlid S71, Hayes RB72, Hofer P28, Hoffmeister M18, Hopper JL55,73, Hsu WL10, Huang WY12, Hudson TJ74, Hunter DJ41,75, Ibañez-Sanz G13,76,77, Idos GE4, Ingersoll R50, Jackson RD78, Jacobs EJ35, Jenkins MA55, Joshi AD39,41, Joshu CE79, Keku TO80, Key TJ81, Kim HR82, Kobayashi E1, Kolonel LN83, Kooperberg C1, Kühn T43, Küry S22, Kweon SS84,85, Larsson SC86, Laurie CA10, Le Marchand L67, Leal SM87, Lee SC88,89, Lejbkowicz F90,91,92, Lemire M74, Li CI1, Li L93, Lieb W94, Lin Y1, Lindblom A95,96, Lindor NM97, Ling H50, Louie TL10, Männistö S98, Markowitz SD99, Martín V14,100, Masala G101, McNeil CE102, Melas M4, Milne RL55,56, Moreno L17, Murphy N68, Myte R71, Naccarati A103,104, Newcomb PA1,36, Offit K105,106, Ogino S40,41,107,108, Onland-Moret NC54, Pardini B104,109, Parfrey PS110, Pearlman R70, Perduca V111,112, Pharoah PDP52, Pinchev M91, Platz EA79, Prentice RL1, Pugh E50, Raskin L113, Rennert G91,92,114, Rennert HS91,92,114, Riboli E115, Rodríguez-Barranco M14,116, Romm J50, Sakoda LC1,117, Schafmayer C118, Schoen RE119, Seminara D64, Shah M53, Shelford T50, Shin MH84, Shulman K120, Sieri S121, Slattery ML122, Southey MC123, Stadler ZK124, Stegmaier C125, Su YR1, Tangen CM65, Thibodeau SN126, Thomas DC4, Thomas SS1, Toland AE127, Trichopoulou A19,20, Ulrich CM24, Van Den Berg DJ4, van Duijnhoven FJB57, Van Guelpen B71, van Kranen H128, Vijai J124, Visvanathan K79, Vodicka P103,129,130, Vodickova L103,129,130, Vymetalkova V103,129,130, Weigl K18,27,131, Weinstein SJ12, White E1, Win AK32,55, Wolf CR132, Wolk A86,133, Woods MO134, Wu AH4, Zaidi SH74, Zanke BW135, Zhang Q136, Zheng W137, Scacheri PC138, Potter JD1, Bassik MC11, Kundaje A7,11, Casey G139, Moreno V13,14,15,77, Abecasis GR2, Nickerson DA9, Gruber SB4, Hsu L1,10, Peters U140,141.

Author information

1
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
2
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
3
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
4
Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
5
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
6
Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
7
Department of Computer Science, Stanford University, Stanford, CA, USA.
8
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
9
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
10
Department of Biostatistics, University of Washington, Seattle, WA, USA.
11
Department of Genetics, Stanford University, Stanford, CA, USA.
12
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
13
Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
14
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
15
Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
16
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
17
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.
18
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
19
Hellenic Health Foundation, Athens, Greece.
20
WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
21
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
22
Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
23
Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
24
Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
25
Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
26
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
27
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
28
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
29
Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
30
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
31
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
32
Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
33
Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
34
Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA.
35
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
36
Department of Epidemiology, University of Washington, Seattle, WA, USA.
37
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
38
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
39
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
40
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
41
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
42
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
43
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
44
Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
45
Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain.
46
Department of Hematology-Oncology, Chonnam National University Hospital, Hwasun, South Korea.
47
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
48
Department of Surgery and Cancer, Imperial College London, London, UK.
49
Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
50
Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
51
Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ, USA.
52
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
53
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
54
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
55
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
56
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
57
Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands.
58
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
59
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
60
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
61
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
62
International Agency for Research on Cancer, World Health Organization, Lyon, France.
63
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
64
Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
65
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
66
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
67
University of Hawaii Cancer Research Center, Honolulu, HI, USA.
68
Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
69
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
70
Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
71
Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
72
Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA.
73
Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea.
74
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
75
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
76
Gastroenterology Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.
77
Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
78
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA.
79
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
80
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
81
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
82
Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea.
83
Office of Public Health Studies, University of Hawaii Manoa, Honolulu, HI, USA.
84
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
85
Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea.
86
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
87
Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
88
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
89
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
90
The Clalit Health Services, Personalized Genomic Service, Carmel, Haifa, Israel.
91
Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
92
Clalit National Cancer Control Center, Haifa, Israel.
93
Center for Community Health Integration and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
94
Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany.
95
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
96
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
97
Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA.
98
Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
99
Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH, USA.
100
Biomedicine Institute (IBIOMED), University of León, León, Spain.
101
Cancer Risk Factors and Life-Style Epidemiology Unit, Institute of Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
102
USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
103
Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
104
Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
105
Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
106
Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
107
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
108
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
109
Department of Medical Sciences, University of Turin, Turin, Italy.
110
The Clinical Epidemiology Unit, Memorial University Medical School, Newfoundland, Canada.
111
Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France.
112
CESP (Inserm U1018), Facultés de Medicine Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
113
Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
114
Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
115
School of Public Health, Imperial College London, London, UK.
116
Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain.
117
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
118
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
119
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
120
Oncology Unit, Hillel Yaffe Medical Center, Hadera, Israel.
121
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
122
Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
123
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
124
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
125
Saarland Cancer Registry, Saarbrücken, Germany.
126
Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
127
Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
128
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
129
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
130
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
131
Medical Faculty, University of Heidelberg, Heidelberg, Germany.
132
School of Medicine, University of Dundee, Dundee, Scotland, UK.
133
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
134
Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada.
135
Division of Hematology, University of Toronto, Toronto, Ontario, Canada.
136
Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
137
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
138
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA.
139
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
140
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org.
141
Department of Epidemiology, University of Washington, Seattle, WA, USA. upeters@fredhutch.org.

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

PMID:
30510241
DOI:
10.1038/s41588-018-0286-6

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