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
Authors: Watts Eleanor L , Perez-Cornago Aurora , Fensom Georgina K , Smith-Byrne Karl , Noor Urwah , Andrews Colm D , Gunter Marc J , Holmes Michael V , Martin Richard M , Tsilidis Konstantinos K , Albanes Demetrius , Barricarte Aurelio , Bueno-de-Mesquita H Bas , Cohn Barbara A , Deschasaux-Tanguy Melanie , Dimou Niki L , Ferrucci Luigi , Flicker Leon , Freedman Neal D , Giles Graham G , Giovannucci Edward L , Haiman Christopher A , Hankey Graham J , Holly Jeffrey M P , Huang Jiaqi , Huang Wen-Yi , Hurwitz Lauren M , Kaaks Rudolf , Kubo Tatsuhiko , Le Marchand Loic , MacInnis Robert J , Männistö Satu , Metter E Jeffrey , Mikami Kazuya , Mucci Lorelei A , Olsen Anja W , Ozasa Kotaro , Palli Domenico , Penney Kathryn L , Platz Elizabeth A , Pollak Michael N , Roobol Monique J , Schaefer Catherine A , Schenk Jeannette M , Stattin Pär , Tamakoshi Akiko , Thysell Elin , Tsai Chiaojung Jillian , Touvier Mathilde , Van Den Eeden Stephen K , Weiderpass Elisabete , Weinstein Stephanie J , Wilkens Lynne R , Yeap Bu B ,   The PRACTICAL Consortium, CRUK, BPC3, CAPS, PEGASUS, Eeles Rosalind A , Haiman Christopher A , Kote-Jarai Zsofia , Schumacher Fredrick R , Benlloch Sara , Olama Ali Amin Al , Muir Kenneth R , Berndt Sonja I , Conti David V , Wiklund Fredrik , Chanock Stephen , Wang Ying , Tangen Catherine M , Batra Jyotsna , Clements Judith A , Allen Naomi E , Key Timothy J , Travis Ruth C 
Published: June 2022

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.