Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank
Watts EL., Fensom GK., Smith Byrne K., Perez-Cornago A., Allen NE., Knuppel A., Gunter MJ., Holmes MV., Martin RM., Murphy N., Tsilidis KK., Yeap BB., Key TJ., Travis RC.
<jats:p>Background: Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using newly available data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we aimed to investigate the associations of circulating concentrations of IGF-I, sex hormone-binding globulin (SHBG), total and calculated free testosterone with prostate cancer risk. Patients and methods: For prospective analyses of prostate cancer incidence and mortality, we studied 199,698 male UK Biobank participants using Cox proportional hazards models. Multivariable-adjusted hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample of up to 7,776 men. A 2-sample Mendelian randomization (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from 79,148 cases and 61,106 controls from the PRACTICAL consortium. We used cis- and all (cis and trans) SNP MR approaches. Results: After a mean follow-up of 6.9 years, 5,402 men were diagnosed with and 295 died from prostate cancer. Higher circulating IGF-I was associated with an elevated risk (HR per 5 nmol/L increment=1.09, 95% CI 1.05-1.12) and prostate cancer mortality (HR per 5 nmol/L increment=1.15,1.02-1.29) in observational analyses. Cis- and all SNPs MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment=1.34,1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05-1.15), and higher SHBG was associated with a lower risk of prostate cancer (HR per 10 nmol/L increment=0.95,0.94-0.97), but neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. Conclusion(s): These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.</jats:p>