The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.
Whitaker HC., Kote-Jarai Z., Ross-Adams H., Warren AY., Burge J., George A., Bancroft E., Jhavar S., Leongamornlert D., Tymrakiewicz M., Saunders E., Page E., Mitra A., Mitchell G., Lindeman GJ., Evans DG., Blanco I., Mercer C., Rubinstein WS., Clowes V., Douglas F., Hodgson S., Walker L., Donaldson A., Izatt L., Dorkins H., Male A., Tucker K., Stapleton A., Lam J., Kirk J., Lilja H., Easton D., IMPACT Study Steering Committee None., IMPACT Study Collaborators None., UK GPCS Collaborators None., Cooper C., Eeles R., Neal DE.
BACKGROUND: Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. CONCLUSIONS: These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.