The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European Prospective Investigation into Cancer & Nutrition

Background: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancerrisk per unit increase in MSP. This work investigates the association of MSP with prostate cancerrisk using observational and Mendelian randomization(MR) methods. Patients and methods: A nested case-control studywas conducted with the European Prospective Investigationinto Cancerand Nutrition( EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regressionanalysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate canceroverall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method. Results: Plasma MSP concentrations were inversely associated with prostate cancerrisk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stageor histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancerrisk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPICobservational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP. Conclusions: In this large prospective European studyand using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.