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Gastroenterology. 2019 Dec 26. pii: S0016-5085(19)41951-3. doi: 10.1053/j.gastro.2019.12.020. [Epub ahead of print]

Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

Author information

1
Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France. Electronic address: murphyn@iarc.fr.
2
Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
3
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
4
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
5
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.
6
Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
7
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
8
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
9
National Institute for Health Innovation, School of Population Health, The University of Auckland, Auckland, New Zealand.
10
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
11
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
12
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
13
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
14
Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
15
Institute of Medical Research at St. James's, University of Leeds, Leeds, UK.
16
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.
17
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010, Australia; Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
18
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
19
Institute for Health Research, Kaiser Permanente Colorado, Denver, Colorado, USA.
20
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
21
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
22
Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain.
23
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
24
Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
25
Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
26
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
27
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA.
28
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
29
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
30
Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
31
Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
32
Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
33
Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
34
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
35
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Biostatistics, University of Washington, Seattle, Washington, USA.
36
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
37
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
38
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea.
39
University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
40
Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA.
41
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
42
CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Biomedicine Institute (IBIOMED), University of León, León, Spain.
43
Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (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.
44
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; School of Public Health, University of Washington, Seattle, Washington, USA.
45
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
46
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
47
Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
48
CESP (Inserm U1018), Fac. de médecine - Université Paris-Saclay, Fac. de médecine - UVSQ, 94805, Villejuif, France; Gustave Roussy, F-94805, Villejuif, France; Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, France.
49
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
50
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
51
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Centre for Public Health Research, Massey University, Wellington, New Zealand.
52
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.
53
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.
54
Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
55
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
56
Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
57
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
58
Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
59
Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
60
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.
61
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
62
Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
63
University of Southern California, Preventative Medicine, Los Angeles, California, USA.
64
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Abstract

BACKGROUND AIMS:

Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.

METHODS:

Serum levels of IGF1 and other proteins were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 level associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% CI, 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio, 1.08; 95% CI, 1.03-1.12; P=3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI, 1.06-1.18; P =4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in IGFBP3 (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.

CONCLUSIONS:

In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

KEYWORDS:

CRC; GWAS; risk factors; signal transduction

PMID:
31884074
DOI:
10.1053/j.gastro.2019.12.020
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