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 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 None., Allen NE., Key TJ., Travis RC.
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.