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: Insulin-like growth factor-I; Mendelian randomization; aggressive prostate cancer; international consortia; prospective analysis; prostate cancer.

Figure 1

Risks of overall, aggressive* and early-onset† prostate cancer by study-specific fifths of biomarker concentrations (observational only) and 1 SD increment (observational and Mendelian randomization). Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, education status, racial/ethnic group and diabetes status. The position of each square indicates the magnitude of the odds ratio, and the area of the square is proportional to the inverse of the variance of the log odds ratio. The length of the horizontal line through the square indicates the 95% confidence interval. MR risk estimates are estimated using the inverse-variance weighted method for the full instrument methods and the Wald ratio in the cis-SNP analyses. P_trend represents 1-SD increase in biomarker concentration. *Aggressive cancer defined as Gleason grade 8+, or prostate cancer death, or metastases or PSA >100 ng/mL. †Early-onset defined as diagnosed ≤55 years. BMI, body mass index; CI, confidence interval; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor-binding protein; OR, odds ratio; PSA, prostate-specific antigen; SD, standard deviation; MR, Mendelian randomization; SNP, single nucleotide polymorphism

Figure 2

Odds ratio (95% CIs) for overall prostate cancer per study-specific 1-SD increment of IGF-I concentration by subgroup in the EHNBPCCG. Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, education status, racial/ethnic group and diabetes status. The position of each square indicates the magnitude of the odds ratio, and the area of the square is proportional to the inverse of the variance of the log odds ratio. The length of the horizontal line through the square indicates the 95% confidence interval. Tests for heterogeneity for case-defined factors were obtained by fitting separate models for each subgroup and assuming independence of the ORs using a method analogous to a meta-analysis. Tests for heterogeneity for non-case-defined factors were assessed with a χ² test of interaction between subgroup and the binary variable. *Aggressive cancer defined as Gleason grade 8+, or prostate cancer death, or metastases or PSA >100 ng/mL. †Localized defined as TNM stage <T2 with no reported lymph node involvement or metastases or stage I; other localized stage if TNM stage T2 with no reported lymph node involvement or metastases, stage II, or equivalent; advanced stage if they were TNM stage T3 or T4 and/or N1+ and/or M1, stage III–IV or equivalent. ‡ Low grade defined as Gleason score was <7 or equivalent (i.e. extent of differentiation good, moderate); medium grade if Gleason score was 7 (i.e. poorly differentiated); high grade if the Gleason score was ≥8 or equivalent (i.e. undifferentiated). BMI, body mass index; CI, confidence interval; EHNBPCCG, Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group; IGF-I, insulin-like growth factor-I; OR, odds ratio; PSA, prostate-specific antigen; SD, standard deviation; TNM, tumour, node, metastases

Figure 3

Odds ratio (95% CIs) for aggressive* prostate cancer per study-specific 1-SD increment of IGF-I concentration by subgroup in the EHNBPCCG. Estimates are from logistic regression conditioned on the matching variables and adjusted for age, BMI, height, alcohol intake, smoking status, marital status, education status, racial/ethnic group and diabetes status. The position of each square indicates the magnitude of the odds ratio, and the area of the square is proportional to the inverse of the variance of the log odds ratio. The length of the horizontal line through the square indicates the 95% confidence interval. Tests for heterogeneity for case-defined factors were obtained by fitting separate models for each subgroup and assuming independence of the ORs using a method analogous to a meta-analysis. Tests for heterogeneity for non-case-defined factors were assessed with a χ² test of interaction between subgroup and the binary variable. *Aggressive cancer defined as Gleason grade 8+, or prostate cancer death, or metastases or PSA >100 ng/mL. †Localized/other localized defined as TNM stage <T2 with no reported lymph node involvement or metastases or stage I, or TNM stage T2 with no reported lymph node involvement or metastases, stage II, or equivalent; advanced stage if they were TNM stage T3 or T4 and/or N1+ and/or M1, stage III–IV or equivalent. ‡Low/medium grade defined as Gleason score was <8 or equivalent (i.e. extent of differentiation good, moderate, poor); high grade if the Gleason score was ≥8 or equivalent (i.e. undifferentiated). BMI, body mass index; CI, confidence interval; EHNBPCCG, Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group; IGF, insulin-like growth factor-I; OR, odds ratio; PSA, prostate-specific antigen; SD, standard deviation; TNM, tumour, node, metastases