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; Demetrius Albanes; Aurelio Barricarte; H Bas Bueno-de-Mesquita; Barbara A Cohn; Melanie Deschasaux-Tanguy; Niki L Dimou; Luigi Ferrucci; Leon Flicker; Neal D Freedman; Graham G Giles; Edward L Giovannucci; Christopher A Haiman; Graham J Hankey; Jeffrey M P Holly; Jiaqi Huang; Wen-Yi Huang; Lauren M Hurwitz; Rudolf Kaaks; Tatsuhiko Kubo; Loic Le Marchand; Robert J MacInnis; Satu Männistö; E Jeffrey Metter; Kazuya Mikami; Lorelei A Mucci; Anja W Olsen; Kotaro Ozasa; Domenico Palli; Kathryn L Penney; Elizabeth A Platz; Michael N Pollak; Monique J Roobol; Catherine A Schaefer; Jeannette M Schenk; Pär Stattin; Akiko Tamakoshi; Elin Thysell; Chiaojung Jillian Tsai; Mathilde Touvier; Stephen K Van Den Eeden; Elisabete Weiderpass; Stephanie J Weinstein; Lynne R Wilkens; Bu B Yeap; PRACTICAL Consortium, CRUK, BPC3, CAPS, PEGASUS; Naomi E Allen; Timothy J Key; Ruth C. Travis

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, Demetrius Albanes, Aurelio Barricarte, H Bas Bueno-de-Mesquita, Barbara A Cohn, Melanie Deschasaux-Tanguy, Niki L Dimou, Luigi Ferrucci, Leon Flicker, Neal D Freedman, Graham G GilesEdward L Giovannucci, Christopher A Haiman, Graham J Hankey, Jeffrey M P Holly, Jiaqi Huang, Wen-Yi Huang, Lauren M Hurwitz, Rudolf Kaaks, Tatsuhiko Kubo, Loic Le Marchand, Robert J MacInnis, Satu Männistö, E Jeffrey Metter, Kazuya Mikami, Lorelei A Mucci, Anja W Olsen, Kotaro Ozasa, Domenico Palli, Kathryn L Penney, Elizabeth A Platz, Michael N Pollak, Monique J Roobol, Catherine A Schaefer, Jeannette M Schenk, Pär Stattin, Akiko Tamakoshi, Elin Thysell, Chiaojung Jillian Tsai, Mathilde Touvier, Stephen K Van Den Eeden, Elisabete Weiderpass, Stephanie J Weinstein, Lynne R Wilkens, Bu B Yeap, PRACTICAL Consortium, CRUK, BPC3, CAPS, PEGASUS, Naomi E Allen, Timothy J Key, Ruth C. Travis

^*Corresponding author for this work

Department of Public Health - Department of Epidemiology

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33 Citations (Scopus)

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	dyac124
Journal	International Journal of Epidemiology
Volume	52
Issue	1
Pages (from-to)	71-86
Number of pages	16
ISSN	0300-5771
DOIs	https://doi.org/10.1093/ije/dyac124
Publication status	Published - Feb 2023

Keywords

Mendelian randomization
aggressive prostate cancer
insulin-like growth factor-I
international consortia
prospective analysis
prostate cancer
Insulin-like growth factor-I

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10.1093/ije/dyac124Licence: 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., Albanes, D., Barricarte, A., Bueno-de-Mesquita, H. B., Cohn, B. A., Deschasaux-Tanguy, M., Dimou, N. L., Ferrucci, L., Flicker, L., Freedman, N. D., ... Travis, R. C. (2023). 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, 52(1), 71-86. Article dyac124. https://doi.org/10.1093/ije/dyac124

@article{1ad18959c0ce43748e02a0a5ef2dc305,

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.",

keywords = "Mendelian randomization, aggressive prostate cancer, insulin-like growth factor-I, international consortia, prospective analysis, prostate cancer, Insulin-like growth factor-I",

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 Demetrius Albanes and Aurelio Barricarte and Bueno-de-Mesquita, {H Bas} and Cohn, {Barbara A} and Melanie Deschasaux-Tanguy and Dimou, {Niki L} and Luigi Ferrucci and Leon Flicker and Freedman, {Neal D} and Giles, {Graham G} and Giovannucci, {Edward L} and Haiman, {Christopher A} and Hankey, {Graham J} and Holly, {Jeffrey M P} and Jiaqi Huang and Wen-Yi Huang and Hurwitz, {Lauren M} and Rudolf Kaaks and Tatsuhiko Kubo and {Le Marchand}, Loic and MacInnis, {Robert J} and Satu M{\"a}nnist{\"o} and Metter, {E Jeffrey} and Kazuya Mikami and Mucci, {Lorelei A} and Olsen, {Anja W} and Kotaro Ozasa and Domenico Palli and Penney, {Kathryn L} and Platz, {Elizabeth A} and Pollak, {Michael N} and Roobol, {Monique J} and Schaefer, {Catherine A} and Schenk, {Jeannette M} and P{\"a}r Stattin and Akiko Tamakoshi and Elin Thysell and Tsai, {Chiaojung Jillian} and Mathilde Touvier and {Van Den Eeden}, {Stephen K} and Elisabete Weiderpass and Weinstein, {Stephanie J} and Wilkens, {Lynne R} and Yeap, {Bu B} and {PRACTICAL Consortium, CRUK, BPC3, CAPS, PEGASUS} and Allen, {Naomi E} and Key, {Timothy J} and Travis, {Ruth C.}",

year = "2023",

month = feb,

doi = "10.1093/ije/dyac124",

language = "English",

volume = "52",

pages = "71--86",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "1",

}

Watts, EL, Perez-Cornago, A, Fensom, GK, Smith-Byrne, K, Noor, U, Andrews, CD, Gunter, MJ, Holmes, MV, Martin, RM, Tsilidis, KK, Albanes, D, Barricarte, A, Bueno-de-Mesquita, HB, Cohn, BA, Deschasaux-Tanguy, M, Dimou, NL, Ferrucci, L, Flicker, L, Freedman, ND, Giles, GG, Giovannucci, EL, Haiman, CA, Hankey, GJ, Holly, JMP, Huang, J, Huang, W-Y, Hurwitz, LM, Kaaks, R, Kubo, T, Le Marchand, L, MacInnis, RJ, Männistö, S, Metter, EJ, Mikami, K, Mucci, LA, Olsen, AW, Ozasa, K, Palli, D, Penney, KL, Platz, EA, Pollak, MN, Roobol, MJ, Schaefer, CA, Schenk, JM, Stattin, P, Tamakoshi, A, Thysell, E, Tsai, CJ, Touvier, M, Van Den Eeden, SK, Weiderpass, E, Weinstein, SJ, Wilkens, LR, Yeap, BB, PRACTICAL Consortium, CRUK, BPC3, CAPS, PEGASUS, Allen, NE, Key, TJ & Travis, RC 2023, '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. 52, no. 1, dyac124, pp. 71-86. https://doi.org/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. / Watts, Eleanor L; Perez-Cornago, Aurora; Fensom, Georgina K et al.
In: International Journal of Epidemiology, Vol. 52, No. 1, dyac124, 02.2023, p. 71-86.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer

T2 - 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 - Albanes, Demetrius

AU - Barricarte, Aurelio

AU - Bueno-de-Mesquita, H Bas

AU - Cohn, Barbara A

AU - Deschasaux-Tanguy, Melanie

AU - Dimou, Niki L

AU - Ferrucci, Luigi

AU - Flicker, Leon

AU - Freedman, Neal D

AU - Giles, Graham G

AU - Giovannucci, Edward L

AU - Haiman, Christopher A

AU - Hankey, Graham J

AU - Holly, Jeffrey M P

AU - Huang, Jiaqi

AU - Huang, Wen-Yi

AU - Hurwitz, Lauren M

AU - Kaaks, Rudolf

AU - Kubo, Tatsuhiko

AU - Le Marchand, Loic

AU - MacInnis, Robert J

AU - Männistö, Satu

AU - Metter, E Jeffrey

AU - Mikami, Kazuya

AU - Mucci, Lorelei A

AU - Olsen, Anja W

AU - Ozasa, Kotaro

AU - Palli, Domenico

AU - Penney, Kathryn L

AU - Platz, Elizabeth A

AU - Pollak, Michael N

AU - Roobol, Monique J

AU - Schaefer, Catherine A

AU - Schenk, Jeannette M

AU - Stattin, Pär

AU - Tamakoshi, Akiko

AU - Thysell, Elin

AU - Tsai, Chiaojung Jillian

AU - Touvier, Mathilde

AU - Van Den Eeden, Stephen K

AU - Weiderpass, Elisabete

AU - Weinstein, Stephanie J

AU - Wilkens, Lynne R

AU - Yeap, Bu B

AU - PRACTICAL Consortium, CRUK, BPC3, CAPS, PEGASUS

AU - Allen, Naomi E

AU - Key, Timothy J

AU - Travis, Ruth C.

PY - 2023/2

Y1 - 2023/2

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.

KW - Mendelian randomization

KW - aggressive prostate cancer

KW - insulin-like growth factor-I

KW - international consortia

KW - prospective analysis

KW - prostate cancer

KW - Insulin-like growth factor-I

UR - http://www.scopus.com/inward/record.url?scp=85137773721&partnerID=8YFLogxK

U2 - 10.1093/ije/dyac124

DO - 10.1093/ije/dyac124

M3 - Journal article

C2 - 35726641

SN - 0300-5771

VL - 52

SP - 71

EP - 86

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 1

M1 - dyac124

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. 2023 Feb;52(1):71-86. dyac124. Epub 2022 Jun 21. 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

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