Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women.
Mendelian randomization
breast cancer
insulin-like growth factor-1 (IGF-1)
insulin-like growth factor-binding protein-3 (IGFBP-3)
observational
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
17
10
2019
revised:
09
01
2020
accepted:
24
01
2020
pubmed:
15
3
2020
medline:
7
1
2021
entrez:
15
3
2020
Statut:
ppublish
Résumé
Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference. We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls. In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.
Sections du résumé
BACKGROUND
Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference.
PATIENTS AND METHODS
We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls.
RESULTS
In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER
CONCLUSION
Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.
Identifiants
pubmed: 32169310
pii: S0923-7534(20)36019-1
doi: 10.1016/j.annonc.2020.01.066
pmc: PMC7221341
pii:
doi:
Substances chimiques
Insulin-Like Growth Factor Binding Protein 3
0
Insulin-Like Growth Factor I
67763-96-6
Types de publication
Journal Article
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
641-649Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 205212/Z/16/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C8221/A1917
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18281/A19169
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Informations de copyright
Copyright © 2020. Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Disclosure The authors have declared no conflicts of interest.
Références
Genet Epidemiol. 2016 May;40(4):304-14
pubmed: 27061298
Cancer Epidemiol Biomarkers Prev. 2015 Oct;24(10):1439-49
pubmed: 26224798
Eur J Cancer. 1993;29A(4):492-7
pubmed: 8435198
Cancer Res. 1984 May;44(5):2122-8
pubmed: 6324997
J Natl Cancer Inst. 2002 Apr 17;94(8):606-16
pubmed: 11959894
Lancet. 1990 Mar 31;335(8692):765-74
pubmed: 1969518
Lancet. 1998 May 9;351(9113):1393-6
pubmed: 9593409
Am J Epidemiol. 2017 Nov 1;186(9):1026-1034
pubmed: 28641372
Mol Pathol. 2001 Jun;54(3):149-54
pubmed: 11376126
Endocr Relat Cancer. 2005 Dec;12(4):1071-82
pubmed: 16322344
BMJ. 2020 Feb 12;368:m131
pubmed: 32051121
Endocr Rev. 2007 Feb;28(1):20-47
pubmed: 16931767
Nat Rev Cancer. 2008 Dec;8(12):915-28
pubmed: 19029956
Front Endocrinol (Lausanne). 2011 May 16;2:13
pubmed: 22654794
Eur Heart J. 2008 Mar;29(6):800-9
pubmed: 18303034
Int J Epidemiol. 2015 Apr;44(2):512-25
pubmed: 26050253
Int J Cancer. 2016 Oct 1;139(7):1520-33
pubmed: 27225428
Nat Genet. 2018 May;50(5):693-698
pubmed: 29686387
Br J Cancer. 2014 Apr 29;110(9):2361-8
pubmed: 24675382
Int J Epidemiol. 2017 Dec 1;46(6):1734-1739
pubmed: 28398548
Aging Cell. 2016 Oct;15(5):811-24
pubmed: 27329260
Lancet Oncol. 2010 Jun;11(6):530-42
pubmed: 20472501
Am J Epidemiol. 1999 Aug 15;150(4):341-53
pubmed: 10453810
Lancet Oncol. 2013 Sep;14(10):1009-19
pubmed: 23890780
Front Oncol. 2018 Apr 16;8:103
pubmed: 29713614
Nature. 2017 Nov 2;551(7678):92-94
pubmed: 29059683
J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):455-69
pubmed: 19031049
Int J Biochem Cell Biol. 1996 Jun;28(6):619-37
pubmed: 8673727