Prospective validation of microseminoprotein-ß added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort.

OBJECTIVES: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-ß (MSP) adds predictive value. PATIENTS AND METHODS: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. RESULTS: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014-0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. CONCLUSION: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.

Prespecified 4-Kallikrein Marker Model at Age 50 or 60 for Early Detection of Lethal Prostate Cancer in a Large Population Based Cohort of Asymptomatic Men Followed for 20 Years.

PURPOSE: A prespecified statistical model based on 4 kallikrein markers in blood, commercially available as the 4Kscore®, has been shown to accurately detect high grade (greater than Grade Group 2) prostate cancer in men with moderately elevated prostate specific antigen. We assessed whether the model predicted prostate cancer metastasis or death in men not subject to prostate specific antigen screening. MATERIALS AND METHODS: The cohort includes 43,692 unscreened prostate cancer-free men from a Swedish population based cohort with low rates of prostate specific antigen screening (Västerbotten Intervention Project). Using cryopreserved blood collected at ages 50 and 60 years from men in this cohort we analyzed the association between prostate specific antigen and other kallikrein marker levels in blood and risk of prostate cancer metastasis or death. RESULTS: There were 308 with metastases and 172 prostate cancer deaths. Baseline prostate specific antigen was strongly associated with 20-year risk of prostate cancer death (c-index at age 50, 0.859, 95% CI 0.799-0.916; age 60, 0.840, 95% CI 0.799-0.878). Men 60 years old with prostate specific antigen below median (less than 1.2 ng/ml) had 0.4% risk of prostate cancer death at 20 years. Among men with moderately elevated prostate specific antigen (2.0 ng/ml or greater) the 4Kscore markedly improved discrimination (c-index 0.767 vs 0.828 and 0.774 vs 0.862 in men age 50 and 60, respectively). Long-term risk of prostate cancer death or metastasis in men with low 4Kscores was very low. CONCLUSIONS: Screening should focus on men in top prostate specific antigen quartile at age 60 years. Men with elevated prostate specific antigen but a low 4Kscore can safely be monitored with repeated blood markers in place of immediate biopsy.

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 and 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 cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods. PATIENTS AND METHODS: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall 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 cancer risk 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 stage or 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 cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 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 study and 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.

Development and validation of a UHPLC-UV method for the determination of a prostate secretory protein 94-derived synthetic peptide (PCK3145) in human plasma and assessment of its stability in human plasma.

PCK3145 is a synthetic peptide, derived from the Prostate Secreted Protein 94 (PSP94), with promising in vitro and animal in vivo results in prostate cancer. The aim of the present study was to develop and validate a fast and robust ultra-high-performance liquid chromatography with ultraviolet detection for the determination of PCK3145 in human plasma which would be suitable for the assessment of PCK3145 stability to proteolytic degradation. Following protein precipitation, chromatographic separation was carried out on an Aeris Peptide C18 column with mobile phase consisting of acetonitrile-water at a flow-rate of 0.50 mL/min. The calibration curve was linear over the range 0.50-20.00 µg/mL. Intra- and inter-day percentage relative standard deviation and relative error were ≤10%. The limit of detection and the lower limit of quantification were 0.15 and 0.50 µg/mL, respectively. Recovery of PCK3145 from human plasma was ≥96%. The peptide presented high stability in whole blood and in human plasma (>98% intact peptide after 24 h incubation at 37°C in human plasma), which represents a distinctive advantage in the therapeutic use of the compound. This is the first validated UHPLC method for the determination of PCK3145 reported, and it was successfully applied in the study of the proteolytic stability of PCK3145 in human plasma ex vivo. Copyright © 2016 John Wiley & Sons, Ltd.

Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study.

BACKGROUND: The prostate-specific antigen (PSA) test is used to screen for prostate cancer but has a high false-positive rate that translates into unnecessary prostate biopsies and overdiagnosis of low-risk prostate cancers. We aimed to develop and validate a model to identify high-risk prostate cancer (with a Gleason score of at least 7) with better test characteristics than that provided by PSA screening alone. METHODS: The Stockholm 3 (STHLM3) study is a prospective, population-based, paired, screen-positive, diagnostic study of men without prostate cancer aged 50-69 years randomly invited by date of birth from the Swedish Population Register kept by the Swedish Tax Agency. Men with prostate cancer at enrolment were excluded from the study. The predefined STHLM3 model (a combination of plasma protein biomarkers [PSA, free PSA, intact PSA, hK2, MSMB, MIC1], genetic polymorphisms [232 SNPs], and clinical variables [age, family, history, previous prostate biopsy, prostate exam]), and PSA concentration were both tested in all participants enrolled. The primary aim was to increase the specificity compared with PSA without decreasing the sensitivity to diagnose high-risk prostate cancer. The primary outcomes were number of detected high-risk cancers (sensitivity) and the number of performed prostate biopsies (specificity). The STHLM3 training cohort was used to train the STHLM3 model, which was prospectively tested in the STHLM3 validation cohort. Logistic regression was used to test for associations between biomarkers and clinical variables and prostate cancer with a Gleason score of at least 7. This study is registered with ISCRTN.com, number ISRCTN84445406. FINDINGS: The STHLM3 model performed significantly better than PSA alone for detection of cancers with a Gleason score of at least 7 (p<0·0001), the area under the curve was 0·56 (95% CI 0·55-0·60) with PSA alone and 0·74 (95% CI 0·72-0·75) with the STHLM3 model. All variables used in the STHLM3 model were significantly associated with prostate cancers with a Gleason score of at least 7 (p<0·05) in a multiple logistic regression model. At the same level of sensitivity as the PSA test using a cutoff of ≥3 ng/mL to diagnose high risk prostate cancer, use of the STHLM3 model could reduce the number of biopsies by 32% (95% CI 24-39) and could avoid 44% (35-54) of benign biopsies. INTERPRETATION: The STHLM3 model could reduce unnecessary biopsies without compromising the ability to diagnose prostate cancer with a Gleason score of at least 7, and could be a step towards personalised risk-based prostate cancer diagnostic programmes. FUNDING: Stockholm County Council (Stockholms Läns Landsting).

A functional polymorphism in MSMB gene promoter is associated with prostate cancer risk and serum MSMB expression.

BACKGROUND: To explore the reported association of SNP marker rs10993994 with prostate cancer identified by two independent in two genome-wide association studies (GWAS) further, we performed a case-control study in southern Chinese Han population. Consequently, we detected the serum levels of MSMB expression with different genotypes in the cases and controls to characterize the functional consequences of rs10993994. MATERIALS AND METHODS: Two hundred fifty-one prostate cancer and 258 control subjects were included in the cancer association study and 90 serum samples were used to test the expression of the MSMB by Enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that the T allele displayed an increased prevalence of prostate cancer compared with the C allele (OR = 1.30, 95% CI = 1.01-1.67, P = 0.040). Moreover, the prostate cancer patients carrying CT/TT genotype had significantly decreased serum MSMB levels compared to those with CC genotype (16.32 +/- 3.98 microg/L vs. 19.33 +/- 4.27 microg/L, P = 0.022). CONCLUSIONS: rs10993994 in MSMB promoter affects serum MSMB expression, contributes to the genetic predisposition to prostate cancer in southern Chinese Han population.

A Four-kallikrein Panel and ß-Microseminoprotein in Predicting High-grade Prostate Cancer on Biopsy: An Independent Replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™. OBJECTIVE: To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether ß-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. DESIGN, SETTING, AND PARTICIPANTS: Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The predictive accuracy of prespecified prediction models was compared with biopsy outcomes. RESULTS AND LIMITATIONS: Among men with PSA of 4.0-25ng/ml, 1111 had prostate cancer, 318 of whom had high-grade disease. Total PSA and age predicted high-grade cancer with an area under the curve of 0.648 (95% confidence interval [CI] 0.614-0.681) and the four-kallikrein panel increased discrimination to 0.746 (95% CI 0.717-0.774). Adding MSP to the four-kallikrein panel led to a significant (Wald test; p=0.015) but small increase (0.003) in discrimination. Limitations include a risk of verification bias among men with PSA of 3.0-3.99ng/ml and the absence of digital rectal examination results. CONCLUSIONS: These findings provide additional evidence that kallikrein markers can be used to inform biopsy decision-making. Further studies are needed to define the role of MSP. PATIENT SUMMARY: Four kallikrein markers and ß-microseminoprotein in blood improve discrimination of high-grade prostate cancer at biopsy in men with elevated prostate-specific antigen.

Screening of biomarkers for liver adenoma in low-dose-rate γ-ray-irradiated mice.

PURPOSE: Chronic low-dose-rate (20 mGy/day) γ-irradiation increases the incidence of hepatocellular adenomas (HCA) in female B6C3F1 mice. The purpose of this study is to identify potential serum biomarkers for these HCAs by a new approach. MATERIAL AND METHODS: Microarray analysis were performed to compare the gene expression profiles of HCAs from mice exposed to low-dose-rate γ-rays with those of normal livers from non-irradiated mice. From the differentially expressed genes, those for possibly secretory proteins were selected. Then, the levels of the proteins in sera were analysed by ELISA. RESULTS: Microarray analysis identified 4181 genes differentially expressed in HCAs (>2.0-fold). From these genes, those for α-fetoprotein (Afp), α-1B-glycoprotein (A1bg) and serine peptidase inhibitor Kazal type-3 (Spink3) were selected as the genes for candidate proteins. ELISA revealed that the levels of Afp and A1bg proteins in sera significantly increased and decreased, respectively, in low-dose-rate irradiated mice with HCAs and also same tendency was observed in human patients with hepatocellular carcinomas. CONCLUSION: These results indicate that A1bg could be a new serum biomarker for liver tumor. This new approach of using microarray to select genes for secretory proteins is useful for prediction of novel tumor markers in sera.

Prognostic value of prostate secretory protein of 94 amino acids and its binding protein after radical prostatectomy.

PURPOSE: To establish the prognostic value of total and free prostate secretory protein of 94 amino acids (PSP94) and the PSP94-binding protein (PSPBP) following radical prostatectomy. EXPERIMENTAL DESIGN: One hundred and eighty-five serum samples were obtained from patients with localized prostate cancer prior to treatment with radical prostatectomy at Virginia Urology (Richmond, VA). Patients were followed up for a median of 48 months (range, 1-66 months) and biochemical relapse was indicated as total prostate-specific antigen (tPSA) levels increasing to > 0.1 ng/mL. The available clinical variables included initial tPSA, Gleason score, surgical margin status, and clinical stage. Total PSP94, free PSP94, and the PSPBP were quantified in the pretreatment serum using new ELISA tests (Medicorp, Inc. and Ambrilia Biopharma, Inc., Montreal, Quebec, Canada). Univariate and multivariate Cox proportional hazards models were used to assess the ability of PSP94 and PSPBP to predict time to recurrence. RESULTS: Thirty-one patients had biochemical recurrence. Gleason score, margin status, clinical stage, and initial tPSA significantly predicted recurrence risk (all P < 0.001). In addition, PSPBP was negatively associated with recurrence risk (P = 0.005), and, consistent with previous studies, the bound/free PSP94 ratio was positively associated with recurrence risk (P = 0.008). Multivariate analysis showed that PSPBP, as well as the bound/free PSP94 ratio, were independent predictors of biochemical relapse risk adjusting for tPSA, Gleason score, and margin status. CONCLUSIONS: Bound/free PSP94 and PSPBP are novel and independent prognostic markers following radical prostatectomy for prostate cancer.

Establishment of a serum tumor marker for preclinical trials of mouse prostate cancer models.

Current prostate cancer research in both basic and preclinical trial studies employ genetically engineered mouse models. However, unlike in human prostate cancer patients, rodents have no counterpart of prostatic-specific antigen (PSA) for monitoring prostate cancer initiation and progression. In this study, we established a mouse serum tumor marker from a mouse homologue of human prostate secretory protein of 94 amino acids (PSP94). Immunohistochemistry studies on different histologic grades from both transgenic and knock-in mouse prostate cancer models showed the down-regulation of tissue PSP94 expression (P < 0.001), the same as for PSA and PSP94 in humans. The presence of mouse serum PSP94 was shown by affinity column and immunoprecipitation purification using a polyclonal mouse PSP94 antibody. A competitive ELISA protocol was established to quantify serum PSP94 levels with a sensitivity of 1 ng/mL. Quantified serum levels of mouse PSP94 ranged from 49.84 ng/mL in wild-type mice to 113.86, 400.45, and 930.90 ng/mL in mouse prostatic intraepithelial neoplasia with microinvasion, well differentiated, moderately differentiated, and poorly differentiated prostate cancer genetically engineered prostate cancer mice, respectively (P < 0.01, n = 68). This increase in serum PSP94 is also well correlated with age and tumor weight. Through longitudinal monitoring of serum PSP94 levels of castrated mice (androgen ablation therapy), we found a correlation between responsiveness/refractory prostate tissues and serum PSP94 levels. The utility of mouse serum PSP94 as a marker in hormone therapy was further confirmed by three-dimensional ultrasound imaging. The establishment of the first rodent prostate cancer serum biomarker will greatly facilitate both basic and preclinical research on human prostate cancer.

A Four-kallikrein Panel Predicts High-grade Cancer on Biopsy: Independent Validation in a Community Cohort.

BACKGROUND: A statistical model based on four kallikrein markers (total prostate-specific antigen [tPSA], free PSA [fPSA], intact PSA, and human kallikrein-related peptidase 2) in blood can predict risk of Gleason score ≥7 (high-grade) cancer at prostate biopsy. OBJECTIVE: To determine the value of this model in predicting high-grade cancer at biopsy in a community-based setting in which referral criteria included percentage of fPSA to tPSA (%fPSA). DESIGN, SETTING, AND PARTICIPANTS: We evaluated the model, with or without adding blood levels of microseminoprotein-ß (MSMB) in a cohort of 749 men referred for prostate biopsy due to elevated PSA (≥3 ng/ml), low %fPSA (<20%), or suspicious digital rectal examination at Skåne University Hospital, Malmö, Sweden. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The kallikrein markers, with or without MSMB levels, measured in cryopreserved anticoagulated blood were combined with age in a published statistical model (Prostate Testing for Cancer and Treatment [ProtecT]) to predict high-grade cancer at biopsy. Predictive accuracy was compared with a base model. RESULTS AND LIMITATIONS: The %fPSA was low (median: 17; interquartile range: 13-22) in this cohort because this marker was used as a referral criterion. The ProtecT model improved discrimination over age and PSA for high-grade cancer (0.777 vs 0.720; p=0.002). At one illustrative cut point, use of the panel would reduce the number of biopsies by 236 per 1000 and detect 195 of 208 (94%) but delay diagnosis of 13 of 208 high-grade cancers. MSMB levels in blood did not improve the accuracy of the panel (p=0.2). CONCLUSIONS: The kallikrein model is predictive of high-grade cancer if criteria for biopsy referral also include %fPSA, and it can reduce unnecessary biopsies without missing an undue number of tumors. PATIENT SUMMARY: We evaluated a published model to predict biopsy outcome in men biopsied due to low percentage of free to total prostate-specific antigen. The model helps reduce unnecessary biopsies without missing an undue number of high-grade cancers.

Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer.

Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.

Prognostic significance of surfactant protein A, surfactant protein D, Clara cell protein 16, S100 protein, trefoil factor 3, and prostatic secretory protein 94 in idiopathic pulmonary fibrosis, sarcoidosis, and chronic pulmonary obstructive disease.

BACKGROUND: Identification of serum and bronchoalveolar lavage fluid (BALF) biomarkers may facilitate diagnosis and prognostication in various lung disorders. OBJECTIVE: Serum and BALF levels of surfactant protein A (SP-A), surfactant protein D (SP-D), Clara cell protein 16 (CC16), S100 protein, trefoil factor 3 (TFF3), and prostatic secretory protein 94 (PSP94) were evaluated in 94 consecutive patients (idiopathic pulmonary fibrosis (IPF; n=18), sarcoidosis (n=25), chronic obstructive pulmonary disease (COPD; n=51)), and in 155 healthy controls. METHODS: Biomarkers were measured at diagnosis and compared with disease characteristics. Both uniparametric and multiparametric analyses were used. RESULTS: Seven significant correlations were found: 1) BALF PSP94 level correlated with prognosis of sarcoidosis (P=0.035); 2) BALF SP-D level with pulmonary functions in IPF (P=0.032); 3) BALF SP-D and TFF3 with IPF mortality (P=0.049 and 0.017, respectively); 4) serum TFF3 level with COPD mortality (P=0.006,); 5) serum SP-A with pulmonary functions impairment in IPF (P=0.011); 6) serum SP-D level was associated with HRCT interstitial score in IPF (P=0.0346); and 7) serum SP-A was associated with staging of COPD according to spirometry (P<0.001). Moreover, our analysis showed that some biomarker levels differed significantly among the diseases: 1) BALF SP-D level differed between sarcoidosis and IPF; 2) serum SP-A level differed among IPF, sarcoidosis, COPD and was also different from healthy controls; 3) serum S100A6, S100A11 levels differed among IPF, sarcoidosis, COPD from healthy controls 4) serum SP-D, CC16, TFF-3 levels distinguished IPF patients from healthy controls; and 5) serum CC16, TFF3, PSP94 distinguished COPD patients from healthy controls. Our study shows that some of selected biomarkers should have prognostic value in the analysed lung disorders. On the other hand, these biomarkers do not appear to be unequivocally suitable for differential diagnosis of these disorders.

Development of an ELISA for sPSP94 and utility of the sPSP94/sPSA ratio as a diagnostic indicator to differentiate between benign prostatic hyperplasia and prostate cancer.

BACKGROUND: The serum PSA (sPSA) test has low specificity for prostate cancer (PCa), since sPSA also rises in benign prostatic hyperplasia (BPH). Serum PSP94 (sPSP94), a major secreted prostate protein, is indicated as a PCa marker. The potential of sPSP94 and sPSA in conjunction with each other to improve specificity of diagnostic test for PCa needs to be evaluated. METHODS: PCa patients (n=33), BPH patients (n=44) and healthy controls (n=50) were recruited. A serum-based sandwich ELISA was developed to measure sPSP94 concentrations. Utility of sPSP94 in improving specificity of sPSA test was evaluated by studying sPSP94/sPSA ratios of study participants. RESULTS: Considerable decrease in overlap among sPSP94/sPSA ratio values of BPH and PCa patients was observed, as compared to sPSP94 or sPSA alone. For differentiating between BPH and PCa patients, this ratio had a maximum area under the curve (AUC) of 0.859 (P=0.0132) and had a comparable sensitivity (90.91%) to sPSA with an increased specificity of 70.45%. Further, decision curve analysis (DCA) showed that sPSP94/sPSA ratio had a superior net benefit in identifying PCa, in patients opting for biopsy. CONCLUSION: The sPSP94/sPSA ratio can be a better differentiating marker between BPH and PCa, than sPSP94 or sPSA alone.

Levels of beta-microseminoprotein in blood and risk of prostate cancer in multiple populations.

BACKGROUND: A common genetic variant (rs10993994) in the 5' region of the gene encoding ß-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated. METHODS: We investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided. RESULTS: In all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA. CONCLUSIONS: Regardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.

[Alternative tests to PSA for prostate cancer diagnosis]. / Nuovi test in competizione con il PSA per la diagnosidel carcinoma prostatico.

Prostate specific antigen (PSA) is still the most useful tool to select the population requiring prostatebiopsy. The main downsides of PSA are an inadequate sensitivity to be used in screening and a low specificity for cancer detection. So far, a limited value for PSA derivates (velocity, density, free, proisoforms and doubling time) has been recognised. We present a short review of the literature describing a selection of the most promising alternatives to PSA being studied currently: PCA3, serum kallikreins, serum detectable prostate specific membrane antigen, the nuclear matrix protein EPCA, EPCA-2, prostatic acid phosphatase, urine detectable GSTP1, anti-AMACR antibodies, sarcosine, plasminogen activating urokinase, IGFBP, TGF beta 1,PSP94, IL6, plasmatic DNA, serum autoantibodies, neuroendocrine markers, proteomic analysis.

A common prostate cancer risk variant 5' of microseminoprotein-beta (MSMB) is a strong predictor of circulating beta-microseminoprotein (MSP) levels in multiple populations.

BACKGROUND: ß-Microseminoprotein (MSP) is one of the three most abundantly secreted proteins of the prostate and has been suggested as a biomarker for prostate cancer risk. A common variant, rs10993994, in the 5' region of the gene that encodes MSP (MSMB) has recently been identified as a risk factor for prostate cancer. METHODS: We examined the association between rs10993994 genotype and MSP levels in a sample of 500 prostate cancer-free men from four racial/ethnic populations in the Multiethnic Cohort (European Americans, African Americans, Latinos, and Japanese Americans). Generalized linear models were used to estimate the association between rs10993994 genotype and MSP levels. RESULTS: We observed robust associations between rs10994994 genotype and MSP levels in each racial/ethnic population (all P < 10(-8)), with carriers of the C allele having lower geometric mean MSP levels (ng/mL; CC/CT/TT genotypes: European Americans, 28.8/20.9/10.0; African Americans, 29.0/21.9/10.9; Latinos, 29.2/17.1/8.3; and Japanese Americans, 25.8/16.4/6.7). We estimated the variant accounts for 30% to 50% of the variation in MSP levels in each population. We also observed significant differences in MSP levels between populations (P = 3.5 × 10(-6)), with MSP levels observed to be highest in African Americans and lowest in Japanese Americans. CONCLUSIONS: Rs10993994 genotype is strongly associated with plasma MSP levels in multiple racial/ethnic populations. IMPACT: This supports the hypothesis that rs10993994 may be the biologically functional allele.

Polymorphisms at the Microseminoprotein-beta locus associated with physiologic variation in beta-microseminoprotein and prostate-specific antigen levels.

BACKGROUND: rs10993994, a single nucleotide polymorphism (SNP) at the genetic locus encoding beta-microseminoprotein (beta-MSP), is associated with both prostate cancer risk and levels of blood prostate-specific antigen (PSA), a biomarker used in prostate cancer screening. Therefore, we wished to determine the association between SNPs at MSMB, the gene encoding beta-MSP, and the levels of prostate-produced biomarkers beta-MSP, PSA, and human kallikrein 2 (hK2) in blood and semen. METHODS: Blood and semen from 304 healthy young Swedish men (ages 18-21) were assayed for beta-MSP, PSA, and hK2. SNPs around MSMB were genotyped from matched DNA and analyzed for quantitative association with biomarker levels. Empirical P values were multiple test-corrected and the independence of each SNP's effect was determined. RESULTS: rs10993994 was significantly associated with the blood and semen levels of beta-MSP (both P < 1.0 x 10(-7)) and PSA (P = 0.00014 and P = 0.0019), and semen levels of hK2 (P = 0.00027). Additional copies of the prostate cancer risk allele resulted in lower beta-MSP but higher PSA levels, and singly explained 23% and 5% of the variation seen in semen beta-MSP and PSA, respectively. Additional SNPs at MSMB are associated with beta-MSP and PSA independently of rs10993994. CONCLUSIONS: SNPs at MSMB correlate with physiologic variation in beta-MSP and PSA levels in the blood and semen of healthy young Swedish men. In particular, rs10993994 has a strong effect on beta-MSP levels. IMPACT: Our results suggest a mechanism by which rs10993994 might predispose to prostate cancer and raise the possibility that genetic variation might need to be considered in interpreting the levels of these biomarkers.

Beta-microseminoprotein in serum correlates with the levels in seminal plasma of young, healthy males.

Beta-microseminoprotein (MSP) is one of the most abundant proteins secreted by the prostate gland. Because MSP is also synthesized in nonreproductive organs, the establishment of a solid relationship between the levels of MSP in serum and semen is crucial for future studies connecting MSP with aging or diseases of the prostate gland. We developed a specific, competitive, europium-based immunoassay to measure MSP in serum and seminal plasma. We also produced recombinant MSP in insect cells using baculo virus and purified it to homogeneity by a novel approach with ethanol extraction and gel filtration. The median values of MSP in 205 young men were 12 microg/L (2.5-97.5 percentile, 4.9-26 microg/L) in serum and 0.53 g/L (2.5-97.5 percentile, 0.13-2.0 g/L) or 1.8 mg (2.5-97.5 percentile, 0.32-6.6 mg) in seminal plasma. MSP in serum showed significant correlation to MSP in seminal plasma (r = .50, P < .001). Significant correlations were also found in seminal plasma between MSP and prostate-specific antigen (PSA) (r = .65, P < .001) and between MSP and Zn(2+) (r = .54, P < .001). The yield of recombinant MSP in culture medium was 35 mg/L or higher, and recovery following ethanol extraction was 80%-90%. MSP in serum reflects the prostate secretion of MSP, and correlations were also found in seminal plasma between MSP and PSA and Zn(2+). This suggests that MSP in serum can be used as a marker of prostate secretion, despite the contribution from extra prostatic tissues.

A novel serum marker, total prostate secretory protein of 94 amino acids, improves prostate cancer detection and helps identify high grade cancers at diagnosis.

PURPOSE: New biomarkers for prostate cancer are needed. We determined whether a novel serum marker, total PSP94 can be used to accomplish these goals. MATERIALS AND METHODS: We conducted a case-control study of 1,212 men with no previous history of prostate cancer and who underwent a prostate biopsy from 1998 to 2000 because of an increased PSA or an abnormal DRE. Serum PSP94 levels were assessed using a sandwich enzyme-linked immunosorbent assay technique. Cases were patients with prostate cancer, and controls were patients who had no evidence of cancer. Multivariate logistic regression analysis was used to determine whether or not PSP94 levels improved the predictive value for prostate cancer. RESULTS: Of the 1,212 men 596 (49.2%) had cancer detected. The median PSP94 level was significantly lower among cases (2.60 ng/ml) than among controls (3.40 ng/ml, p <0.0001). The adjusted odds ratios for the presence of prostate cancer for patients with the lowest quartile of PSP94, compared to patients in the highest quartile was 2.70 (95% CI 1.8 - 4.0, p <0.0001). Among a subgroup of 649 men in whom PSA had a low predictive value (PSA less than 20 ng/ml, normal DRE and less than 70 years), 260 (40.1%) were found to have cancer. In this subgroup total PSP94 levels helped discriminate between patients with high grade disease (Gleason score 8 or more, median 1.90 ng/ml), moderate grade disease (Gleason score 7, median 2.34 ng/ml) and low grade disease (Gleason score 6 or less, median 2.60 ng/ml, p = 0.007). PSA and the FTPSA were not able to distinguish between patients with different grades in this group. CONCLUSIONS: Patients with low total PSP94 levels had a high probability for having prostate cancer detected at biopsy. The total PSP94 level was able to help identify patients with high grade disease among a subset of patients in whom PSA and FTPSA are least informative.