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

Neil Murphy, Robert Carreras-Torres, Mingyang Song, Andrew T Chan, Richard M Martin, Nikos Papadimitriou, Niki Dimou, Konstantinos K Tsilidis, Barbara Banbury, Kathryn E Bradbury, Jelena Besevic, Sabina Rinaldi, Elio Riboli, Amanda J Cross, Ruth C Travis, Claudia Agnoli, Demetrius Albanes, Sonja I Berndt, Stéphane Bézieau, D Timothy Bishop, Hermann Brenner, Daniel D Buchanan, N Charlotte Onland-Moret, Andrea Burnett-Hartman, Peter T Campbell, Graham Casey, Sergi Castellví-Bel, Jenny Chang-Claude, María-Dolores Chirlaque, Albert de la Chapelle, Dallas English, Jane C Figueiredo, Steven J Gallinger, Graham G Giles, Stephen B Gruber, Andrea Gsur, Jochen Hampe, Heather Hampel, Tabitha A Harrison, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R Huyghe, Mark A Jenkins, Temitope O Keku, Tilman Kühn, Sun-Seog Kweon, Loic Le Marchand, Christopher I Li, Li Li, Annika Lindblom, Vicente Martín, Roger L Milne, Victor Moreno, Polly A Newcomb, Kenneth Offit, Shuji Ogino, Jennifer Ose, Vittorio Perduca, Amanda I Phipps, Elizabeth A Platz, John D Potter, Conghui Qu, Gad Rennert, Lori C Sakoda, Clemens Schafmayer, Robert E Schoen, Martha L Slattery, Catherine M Tangen, Cornelia M Ulrich, Franzel J B van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Hansong Wang, Emily White, Alicja Wolk, Michael O Woods, Anna H Wu, Wei Zheng, Ulrike Peters, Marc J Gunter, Neil Murphy, Robert Carreras-Torres, Mingyang Song, Andrew T Chan, Richard M Martin, Nikos Papadimitriou, Niki Dimou, Konstantinos K Tsilidis, Barbara Banbury, Kathryn E Bradbury, Jelena Besevic, Sabina Rinaldi, Elio Riboli, Amanda J Cross, Ruth C Travis, Claudia Agnoli, Demetrius Albanes, Sonja I Berndt, Stéphane Bézieau, D Timothy Bishop, Hermann Brenner, Daniel D Buchanan, N Charlotte Onland-Moret, Andrea Burnett-Hartman, Peter T Campbell, Graham Casey, Sergi Castellví-Bel, Jenny Chang-Claude, María-Dolores Chirlaque, Albert de la Chapelle, Dallas English, Jane C Figueiredo, Steven J Gallinger, Graham G Giles, Stephen B Gruber, Andrea Gsur, Jochen Hampe, Heather Hampel, Tabitha A Harrison, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R Huyghe, Mark A Jenkins, Temitope O Keku, Tilman Kühn, Sun-Seog Kweon, Loic Le Marchand, Christopher I Li, Li Li, Annika Lindblom, Vicente Martín, Roger L Milne, Victor Moreno, Polly A Newcomb, Kenneth Offit, Shuji Ogino, Jennifer Ose, Vittorio Perduca, Amanda I Phipps, Elizabeth A Platz, John D Potter, Conghui Qu, Gad Rennert, Lori C Sakoda, Clemens Schafmayer, Robert E Schoen, Martha L Slattery, Catherine M Tangen, Cornelia M Ulrich, Franzel J B van Duijnhoven, Bethany Van Guelpen, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Hansong Wang, Emily White, Alicja Wolk, Michael O Woods, Anna H Wu, Wei Zheng, Ulrike Peters, Marc J Gunter

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 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.

Keywords: CRC; GWAS; Risk Factors; Signal Transduction.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Subgroup analyses of the association between circulating IGF1 levels and colorectal cancer risk in the UK Biobank. HR per 1-SD increment in circulating IGF1 levels. Multivariable Cox regression model using age as the underlying time variable and stratified by sex, Townsend deprivation index (quintiles), region of the recruitment assessment center, and age at recruitment. Models adjusted for waist circumference (per 5 cm), total physical activity (aHRs per SD increment were corrected for regression dilution using a regression dilution ratio (0.76) obtained from the subsample of participants with repeat IGF1 measurements. Median values: height = 176 cm for men and 162 cm for women; CRP = 1.3 mg/L; HbA1c = 35 mmol/mol; testosterone = 1 nmol/L for women and 11.8 nmol/L for men; SHBG = 56.3 nmol/L for men and 37.2 nmol/L for women.
Supplementary Figure 1
Supplementary Figure 1
Funnel plots of risk estimates of (A) IGF1 and (B) IGFBP3 with colorectal cancer against instrumental strength. Instrumental strength is SNP to colorectal cancer effect corrected by SNP to IGF1 or IGFBP3 standard error of the effect. X-axis is in logarithmic scale. P values are 2-sided, MR test.

References

    1. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915.
    1. Samani A.A., Yakar S., LeRoith D. The role of the IGF System in Cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28:20–47.
    1. Kelley K.M., Oh Y., Gargosky S.E. Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol. 1996;28:619–637.
    1. Oh Y., Muller H.L., Ng L. Transforming growth factor- beta-induced cell growth inhibition in human breast cancer cells is mediated through insulin-like growth factor-binding protein-3 action. J Biol Chem. 1995;270:13589–13592.
    1. Baxter R.C. Signalling pathways involved in antiproliferative effects of IGFBP-3: a review. Mol Pathol. 2001;54:145–148.
    1. Ma J., Pollak M.N., Giovannucci E. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst. 1999;91:620–625.
    1. Kaaks R., Toniolo P., Akhmedkhanov A. Serum C-Peptide, Insulin-Like Growth Factor (IGF)-I, IGF-Binding Proteins, and Colorectal Cancer Risk in Women. J Natl Cancer Inst. 2000;92:1592–1600.
    1. Gunter M.J., Hoover D.R., Yu H. Insulin, insulin-like growth factor-i, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res. 2008;68:329–337.
    1. Otani T., Iwasaki M., Sasazuki S. Plasma C-peptide, insulin-like growth factor-I, insulin-like growth factor binding proteins and risk of colorectal cancer in a nested case-control study: the Japan public health center-based prospective study. Int J Cancer. 2007;120:2007–2012.
    1. Palmqvist R., Stattin P., Rinaldi S. Plasma insulin, IGF-binding proteins-1 and -2 and risk of colorectal cancer: a prospective study in northern Sweden. Int J Cancer. 2003;107:89–93.
    1. Rinaldi S., Cleveland R., Norat T. Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies. Int J Cancer. 2010;126:1702–1715.
    1. Probst-Hensch N.M., Yuan J.M., Stanczyk F.Z. IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai. Br J Cancer. 2001;85:1695–1699.
    1. Giovannucci E., Pollak M.N., Platz E.A. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev. 2000;9:345–349.
    1. Wei E.K., Ma J., Pollak M.N. A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2005;14:850–855.
    1. Fred Hutchinson Cancer Research Center Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) Available at:
    1. Allen N., Sudlow C., Downey P. UK Biobank: current status and what it means for epidemiology. Health Policy and Technology. 2012;1:123–126.
    1. UK-Biobank UK Biobank. Protocol for a large-scale prospective epidemiological resources. 2010. Available at: Accessed April 1, 2018.
    1. Hosgood H.D., Gunter M.J., Murphy N. The relation of obesity-related hormonal and cytokine levels with multiple myeloma and non-Hodgkin lymphoma. Front Oncol. 2018;8:103.
    1. UK-Biobank UK Biobank Biomarker Project - Companion Document to Accompany Serum Biomarker Data. Prepared for: UK Biobank Showcase. 2019;Volume 1 Available at: . Accessed June 1, 2019.
    1. Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika. 1982;69:239–241.
    1. Clarke R., Shipley M., Lewington S. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999;150:341–353.
    1. MacMahon S., Peto R., Collins R. Blood pressure, stroke, and coronary heart disease: Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–774.
    1. Clarke R., Emberson J.R., Breeze E. Biomarkers of inflammation predict both vascular and non-vascular mortality in older men. Eur Heart J. 2008;29:800–809.
    1. Murphy N., Strickler H.D., Stanczyk F.Z. A prospective evaluation of endogenous sex hormone levels and colorectal cancer risk in postmenopausal women. J Natl Cancer Inst. 2015;107(10)
    1. Aleksandrova K., Jenab M., Boeing H. Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European prospective investigation into cancer and nutrition. Am J Epidemiol. 2010;172:407–418.
    1. Mori N., Sawada N., Iwasaki M. Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: the JPHC nested case–control study. Int J Cancer. 2019;145:1238–1244.
    1. Rinaldi S., Rohrmann S., Jenab M. Glycosylated hemoglobin and risk of colorectal cancer in men and women, the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2008;17:3108–3115.
    1. Harrell F. Springer; New York: 2001. Regression Modeling Strategies: With applications to linear models, logistic regression, and survival analysis.
    1. Sinnott-Armstrong N., Tanigawa Y., Amar D. Genetics of 38 blood and urine biomarkers in the UK Biobank. bioRxiv. 2019:660506.
    1. Teumer A., Qi Q., Nethander M. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell. 2016;15:811–824.
    1. Huyghe J.R., Bien S.A., Harrison T.A. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 2019;51:76–87.
    1. Brion M.-J.A., Shakhbazov K., Visscher P.M. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013;42:1497–1501.
    1. Burgess S., Butterworth A., Thompson S.G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genetic Epidemiol. 2013;37:658–665.
    1. Burgess S., Scott R.A., Timpson N.J. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30:543–552.
    1. Bowden J., Davey Smith G., Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–525.
    1. Bowden J., Davey Smith G., Haycock P.C. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40:304–314.
    1. Verbanck M., Chen C.-Y., Neale B. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–698.
    1. Davey Smith G., Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23:R89–R98.
    1. Valentinis B., Baserga R. IGF-I receptor signalling in transformation and differentiation. Mol Pathol. 2001;54:133–137.
    1. Sekharam M., Zhao H., Sun M. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-xL Pathway. Cancer Res. 2003;63:7708–7716.
    1. Lahm H., Amstad P., Wyniger J. Blockade of the insulin-like growth-factor-I receptor inhibits growth of human colorectal cancer cells: evidence of a functional IGF-II-mediated autocrine loop. Int J Cancer. 1994;58:452–459.
    1. Levine Morgan E., Suarez Jorge A., Brandhorst S. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014;19:407–417.
    1. Bradbury K.E., Balkwill A., Tipper S.J. The association of plasma IGF-I with dietary, lifestyle, anthropometric, and early life factors in postmenopausal women. Growth Horm IGF Res. 2015;25:90–95.
    1. Zhu K., Meng X., Kerr D.A. The effects of a two-year randomized, controlled trial of whey protein supplementation on bone structure, IGF-1, and urinary calcium excretion in older postmenopausal women. J Bone Miner Res. 2011;26:2298–2306.
    1. Nishida Y., Matsubara T., Tobina T. Effect of low-intensity aerobic exercise on insulin-like growth factor-I and insulin-like growth factor-binding proteins in healthy men. Int J Endocrinol. 2010;2010:452820.
    1. Vigneri P.G., Tirrò E., Pennisi M.S. The insulin/IGF system in colorectal cancer development and resistance to therapy. Front Oncol. 2015;5:230.
    1. Deal C., Ma J., Wilkin Fo. Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators1. J Clin Endocrinol Metab. 2001;86:1274–1280.
    1. Kamat M.A., Blackshaw J.A., Young R. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019;35:4851–4853.
    1. Cui H., Cruz-Correa M., Giardiello F.M. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science. 2003;299:1753–1755.
    1. Cruz-Correa M., Cui H., Giardiello F.M. Loss of imprinting of insulin growth factor II gene: a potential heritable biomarker for colon neoplasia predisposition. Gastroenterology. 2004;126:964–970.
    1. Unger C., Kramer N., Unterleuthner D. Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms. Oncogene. 2017;36:5341.
    1. Morris J.K., George L.M., Wu T. Insulin-like growth factors and cancer: no role in screening. Evidence from the BUPA study and meta-analysis of prospective epidemiological studies. Br J Cancer. 2006;95:112–117.
    1. Young N.J., Metcalfe C., Gunnell D. A cross-sectional analysis of the association between diet and insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in the United Kingdom. Cancer Causes Control. 2012;23:907–917.
    1. Sinnott−Armstrong N., Tanigawa Y., Amar D. Genetics of 38 blood and urine biomarkers in the UK Biobank. bioRxiv. 2019:660506.
    1. Teumer A., Qi Q., Nethander M. Genomewide meta−analysis identifies loci associated with IGF−I and IGFBP3 levels with impact on age−related traits. Aging Cell. 2016;15:811–824.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner