Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis

Eleanor L. Watts; Aurora Perez-Cornago; Georgina K. Fensom; Karl Smith-Byrne; Urwah Noor; Colm D. Andrews; Marc J. Gunter; Michael V. Holmes; Richard M. Martin; Konstantinos K. Tsilidis; Jyotsna Batra

doi:10.1093/ije/dyac124

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis

Eleanor L. Watts^*, Aurora Perez-Cornago, Georgina K. Fensom, Karl Smith-Byrne, Urwah Noor, Colm D. Andrews, Marc J. Gunter, Michael V. Holmes, Richard M. Martin, Konstantinos K. Tsilidis, Jyotsna Batra

^*Corresponding author for this work

Faculty of Health Sciences & Medicine

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Abstract

Background:
Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer.

Methods:
Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium.

Results:
In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I.

Conclusions:
These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

Original language	English
Article number	dyaf094
Pages (from-to)	71-86
Number of pages	16
Journal	International Journal of Epidemiology
Volume	54
Issue number	3
Early online date	1 Feb 2023
DOIs	https://doi.org/10.1093/ije/dyac124 https://doi.org/10.1093/ije/dyaf094
Publication status	Published - 1 Jun 2025

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Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancerFinal published version, 1.16 MBLicence: CC BY

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Watts, E. L., Perez-Cornago, A., Fensom, G. K., Smith-Byrne, K., Noor, U., Andrews, C. D., Gunter, M. J., Holmes, M. V., Martin, R. M., Tsilidis, K. K., & Batra, J. (2025). Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis. International Journal of Epidemiology, 54(3), 71-86. Article dyaf094. https://doi.org/10.1093/ije/dyac124, https://doi.org/10.1093/ije/dyaf094

@article{3bdb9e5f50b9428492d179ebd7724a58,

title = "Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis",

abstract = "Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.",

author = "Watts, {Eleanor L.} and Aurora Perez-Cornago and Fensom, {Georgina K.} and Karl Smith-Byrne and Urwah Noor and Andrews, {Colm D.} and Gunter, {Marc J.} and Holmes, {Michael V.} and Martin, {Richard M.} and Tsilidis, {Konstantinos K.} and Jyotsna Batra",

note = "Links to the original and corrected versions of work are provided.",

year = "2025",

month = jun,

day = "1",

doi = "10.1093/ije/dyac124",

language = "English",

volume = "54",

pages = "71--86",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Revista Engenharia na Agricultura",

number = "3",

}

Watts, EL, Perez-Cornago, A, Fensom, GK, Smith-Byrne, K, Noor, U, Andrews, CD, Gunter, MJ, Holmes, MV, Martin, RM, Tsilidis, KK & Batra, J 2025, 'Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis', International Journal of Epidemiology, vol. 54, no. 3, dyaf094, pp. 71-86. https://doi.org/10.1093/ije/dyac124, https://doi.org/10.1093/ije/dyaf094

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis. / Watts, Eleanor L.; Perez-Cornago, Aurora; Fensom, Georgina K. et al.
In: International Journal of Epidemiology, Vol. 54, No. 3, dyaf094, 01.06.2025, p. 71-86.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis

AU - Watts, Eleanor L.

AU - Perez-Cornago, Aurora

AU - Fensom, Georgina K.

AU - Smith-Byrne, Karl

AU - Noor, Urwah

AU - Andrews, Colm D.

AU - Gunter, Marc J.

AU - Holmes, Michael V.

AU - Martin, Richard M.

AU - Tsilidis, Konstantinos K.

AU - Batra, Jyotsna

N1 - Links to the original and corrected versions of work are provided.

PY - 2025/6/1

Y1 - 2025/6/1

N2 - Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

AB - Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease.

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U2 - 10.1093/ije/dyac124

DO - 10.1093/ije/dyac124

M3 - Article

AN - SCOPUS:85137773721

SN - 0300-5771

VL - 54

SP - 71

EP - 86

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 3

M1 - dyaf094

ER -

Watts EL, Perez-Cornago A, Fensom GK, Smith-Byrne K, Noor U, Andrews CD et al. Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis. International Journal of Epidemiology. 2025 Jun 1;54(3):71-86. dyaf094. Epub 2023 Feb 1. doi: 10.1093/ije/dyac124, 10.1093/ije/dyaf094

Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: A collaborative analysis of 20 prospective studies and Mendelian randomization analysis

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