Soluble urokinase plasminogen activator receptor as a prognostic marker in men participating in prostate cancer screening

Kjellman A, Akre O, Gustafsson O, H circle divide yer-Hansen G, Lilja H, Norming U, Piironen T, Tornblom M (Department of Clinical Science, Intervention, and Technology; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark; Departments of Clinical Laboratories, Urology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet, Stockholm, Sweden; and Syrinx Bioanalytics Oy, Turku, Finland; formerly at Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Copenhagen, Denmark). Soluble urokinase plasminogen activator receptor as a prognostic marker in men participating in prostate cancer screening. J Intern Med 2010; 269: 299-305. Background. The urokinase plasminogen activator (uPA) system is involved in tissue remodelling processes and is up-regulated in many types of malignancies. We investigated whether serum levels of different forms of soluble uPA receptor (suPAR) are associated with survival and in particular with prostate cancer and cardiovascular disease mortality. Methods. Using time-resolved fluorescence immunoassays, we measured intact suPAR [suPAR(I-III)] and intact plus cleaved suPAR [suPAR(I-III) + suPAR(II-III)] and thus calculated the amount of suPAR(II-III) in serum samples from 375 men participating in a prostate cancer screening trial. A total of 312 men were free of prostate cancer and 63 men had prostate cancer diagnosed at the time of screening. The cohort was followed for 15 years. We assessed survival using Kaplan-Meier estimation and Cox proportional hazards regression. Results. The mean age at blood sampling was 64 years. In total, 152 men died during follow-up. SuPAR(I-III) and suPAR(II-III) were significantly positively associated with mortality (P = 0.001 and P < 0.0001, respectively). In a Cox regression model adjusting for age and prostate cancer status, an increase in suPAR(I-III) and suPAR(II-III) by 1-unit (ln-scale) was associated with a hazard ratio (HR) of 2.26 [95% confidence interval (CI) 1.17-4.35] and 2.53 (95% CI 1.56-4.10), respectively. There was a trend towards an increased risk of death from prostate cancer in screening-detected prostate cancer patients with increased values of either suPAR form. However, this difference was not significant and the association disappeared after adjusting for age, tumour stage, tumour grade and prostate-specific antigen. Being in the highest quartile of any of the suPAR forms was associated with a highly significant increased risk of cardiovascular death, with HR adjusted for age of 3.27 (95% CI 1.38-7.73) for suPAR(I-III) quartile 4 versus quartile 1. Conclusions. High concentrations of serum suPAR(I-III) and suPAR(II-III) were associated with poor overall survival. The association was particularly strong for death from cardiovascular disease. No similar association was found for prostate cancer after adjustment for other prognostic factors.