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
Murphy, Neil; Carreras-Torres, Robert; Song, Mingyang; Chan, Andrew T; Martin, Richard M; Papadimitriou, Nikos; Dimou, Niki; Tsilidis, Konstantinos K; Banbury, Barbara; Bradbury, Kathryn E; Besevic, Jelena; Rinaldi, Sabina; Riboli, Elio; Cross, Amanda J; Travis, Ruth C; Agnoli, Claudia; Albanes, Demetrius; Berndt, Sonja I; Bézieau, Stéphane; Bishop, D Timothy; Brenner, Hermann; Buchanan, Daniel D; Onland-Moret, N Charlotte; Burnett-Hartman, Andrea; Campbell, Peter T; Casey, Graham; Castellví-Bel, Sergi; Chang-Claude, Jenny; Chirlaque, María-Dolores; Chapelle, Albert de la; English, Dallas; Figueiredo, Jane C; Gallinger, Steven J; Giles, Graham G; Gruber, Stephen B; Gsur, Andrea; Hampe, Jochen; Hampel, Heather; Harrison, Tabitha A; Hoffmeister, Michael; Hsu, Li; Huang, Wen-Yi; Huyghe, Jeroen R; Jenkins, Mark A; Keku, Temitope O; Kühn, Tilman; Kweon, Sun-Seog; Le Marchand, Loic; Li, Christopher I; Li, Li; Lindblom, Annika; Martín, Vicente; Milne, Roger L; Moreno, Victor; Newcomb, Polly A; Offit, Kenneth; Ogino, Shuji; Ose, Jennifer; Perduca, Vittorio; Phipps, Amanda I; Platz, Elizabeth A; Potter, John D; Qu, Conghui; Rennert, Gad; Sakoda, Lori C; Schafmayer, Clemens; Schoen, Robert E; Slattery, Martha L; Tangen, Catherine M; Ulrich, Cornelia M; van Duijnhoven, Franzel Jb; Van Guelpen, Bethany; Visvanathan, Kala; Vodicka, Pavel; Vodickova, Ludmila; Vymetalkova, Veronika; Wang, Hansong; White, Emily; Wolk, Alicja; Woods, Michael O; Wu, Anna H; Zheng, Wei; Peters, Ulrike; Gunter, Marc J
(2020) Gastroenterology, volume 158, issue 5, pp. 1300 - 1312.e20
(Article)
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
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or IGFBP3 are associated with colorectal cancer development. Methods: Serum levels of IGF1 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 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [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 × 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 × 10 –5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (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.
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Keywords: CRC, GWAS, Risk Factors, Signal Transduction, Gastroenterology, Hepatology, Journal Article
ISSN: 0016-5085
Publisher: W.B. Saunders Ltd
Note: Funding Information: MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). Funding Information: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Funding Information: Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350,; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). Funding Information: Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institutés Distinguished Professor Award to Alicja Wolk. Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). Funding Information: The Colon Cancer Family Registry (CCFR) Illumina GWAS was supported by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (grant numbers U01 CA122839, R01 CA143247). The CCFR participant recruitment and collection of data and biospecimens used in this study were supported by the NCI/NIH (grant number U01 CA167551) and through NCI/NIH cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (grant number U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (grant number U01/U24 CA074806)’ The content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. Funding Information: NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, U.S. Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Funding Information: NSHDS: Swedish Cancer Society; Cancer Research Foundation in Northern Sweden; Swedish Research Council; J C Kempe Memorial Fund; Faculty of Medicine, Umeå University, Umeå, Sweden; and Cutting-Edge Research Grant from the County Council of Västerbotten, Sweden. Funding Information: SMS and REACH: This work was supported by the National Cancer Institute (grant P01 CA074184 to J.D.P. and P.A.N., grants R01 CA097325, R03 CA153323, and K05 CA152715 to P.A.N., and the National Center for Advancing Translational Sciences at the National Institutes of Health (grant KL2 TR000421 to A.N.B.-H.) Funding Information: NCCCS I & II: We acknowledge funding support for this project from the National Institutes of Health, R01 CA66635 and P30 DK034987. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: SELECT: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers U10 CA37429 (CD Blanke), and UM1 CA182883 (CM Tangen/IM Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Funding: (EPICOLON) This work was supported by grants from Fondo de Investigación Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, P111/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), Fundación Privada Olga Torres, FP7 CHIBCHA Consortium, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Action CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRCItaly and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). Funding Information: COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and the Dutch Cancer Society (UM 2012–5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The Nqplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Funding Information: This work was conducted using the UK Biobank Resource under Application Number 25897 and we express our gratitude to the participants and those involved in building the resource. UK Biobank is an open access resource. Bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. Author contributions: Conceived and designed the experiments: NM, MJG. Analyzed the data: RCT, NM, MJG. This article was written by NM and MJG taking into account the comments and suggestions of the coauthors. All coauthors had the opportunity to comment on the analysis and interpretation of the findings and approved the final version for publication. Funding Information: CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– (grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y León (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: Czech Republic CCS: This work was supported by the Grant Agency of the Czech Republic (grants CZ GA CR: GAP304/10/1286 and 1585) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants AZV 15-27580A and AZV 17-30920A). Funding Information: HCES-CRC: the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI18007-1). Funding Information: Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726. Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish research council; K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2 and the Stockholm County Council (ALF project). Funding Information: CLUE II: We appreciate the continued efforts of the staff members at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE II study. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/cancer , 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. Funding Information: OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: Funding RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, or the Department of Health. Funding Information: CORSA: “Österreichische Nationalbank Jubiläumsfondsprojekt” (12511) and Austrian Research Funding Agency (FFG) grant 829675. Funding Information: CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Funding Information: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, Funding Information: MECC: This work was supported by the National Institutes of Health, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR). Publisher Copyright: © 2020 AGA Institute
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