Benign prostate specific antigen distribution and associations with urological outcomes in community dwelling black and white men.
ABSTRACT: We describe cross-sectional associations of benign prostate specific antigen with clinical urological measures and examined the risk of future urological outcomes in 2 population based cohorts of black and white men, respectively.Two population based cohort studies were established to characterize the natural history of and risk factors for prostate disease progression in white and black male residents of Olmsted County, Minnesota, and Genesee County, Michigan, respectively.The benign prostate specific antigen distribution was similar in black men at a median of 32.9 pg/ml (25th, 75th percentiles 17.3, 68.0) and white men at a median of 32.2 pg/ml (25th, 75th percentiles 16.6, 68.9, respectively). However, it was much lower than in previous reports. For Olmsted County men in the upper quartile of benign prostate specific antigen there was a fifteenfold increased risk of prostate cancer (HR 14.6, 95% CI 3.1-68.6) and a twofold higher risk of treatment for benign prostatic hyperplasia (HR 2.2, 95% CI 1.2-4.2) after adjusting for age. After additional adjustment for baseline prostate specific antigen the association between benign prostate specific antigen and prostate cancer risk was attenuated but remained almost ninefold higher for men in the upper quartile of benign prostate specific antigen (HR 8.7, 95% CI 1.8-42.4). The twofold higher risk of treatment for benign prostatic hyperplasia also remained after adjusting for baseline prostate specific antigen for men in the upper benign prostate specific antigen quartile (HR 1.9, 95% CI 0.9-4.0).Results suggest that increased benign prostate specific antigen may help identify men with prostate cancer and those at risk for benign prostatic hyperplasia treatment.
Project description:In men with symptomatic benign prostatic hyperplasia 5?-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5?-reductase inhibitors. We have found that a third of adult prostate samples do not express 5?-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5?-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5?-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen.Prostate samples from men undergoing transurethral prostate resection were used. We determined 5?-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling.Body mass index and age significantly correlated with methylation of the 5?-reductase type 2 gene promoter (p <0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5?-reductase protein expression (p <0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p <0.01).Increasing age and body mass index correlate with increased 5?-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options.
Project description:Although an increased level of the prostate-specific antigen can be an indication for prostate cancer, other reasons often lead to a high rate of false positive results. Therefore, an additional serological screening of autoantibodies in patients' sera could improve the detection of prostate cancer. We performed protein macroarray screening with sera from 49 prostate cancer patients, 70 patients with benign prostatic hyperplasia and 28 healthy controls and compared the autoimmune response in those groups. We were able to distinguish prostate cancer patients from normal controls with an accuracy of 83.2%, patients with benign prostatic hyperplasia from normal controls with an accuracy of 86.0% and prostate cancer patients from patients with benign prostatic hyperplasia with an accuracy of 70.3%. Combining seroreactivity pattern with a PSA level of higher than 4.0 ng/ml this classification could be improved to an accuracy of 84.1%. For selected proteins we were able to confirm the differential expression by using luminex on 84 samples. We provide a minimally invasive serological method to reduce false positive results in detection of prostate cancer and according to PSA screening to distinguish men with prostate cancer from men with benign prostatic hyperplasia.
Project description:Although an increased level of the prostate-specific antigen can be an indication for prostate cancer, other reasons often lead to a high rate of false positive results. Therefore, an additional serological screening of autoantibodies in patients’ sera could improve the detection of prostate cancer. We performed protein macroarray screening with sera from 49 prostate cancer patients, 70 patients with benign prostatic hyperplasia and 28 healthy controls and compared the autoimmune response in those groups. We were able to distinguish prostate cancer patients from normal controls with an accuracy of 83.2%, patients with benign prostatic hyperplasia from normal controls with an accuracy of 86.0% and prostate cancer patients from patients with benign prostatic hyperplasia with an accuracy of 70.3%. Combining seroreactivity pattern with a PSA level of higher than 4.0 ng/ml this classification could be improved to an accuracy of 84.1%. For selected proteins we were able to confirm the differential expression by using Lluminex on 84 samples. We provide a minimally invasive serological method to reduce false positive results in detection of prostate cancer and according to PSA screening to distinguish men with prostate cancer from men with benign prostatic hyperplasia. Overall design: Comparison of autoantibodies against 1827 E.coli expressed cDNA clones in patients with prostate cancer (n=49), benign prostate hyperplasia (n=70) and healthy controls (n=28)
Project description:<h4>Objective</h4>To assess the role of dutasteride in preventing clinical progression of benign prostatic hyperplasia in asymptomatic men with larger prostates.<h4>Design</h4>Post hoc analysis of four year, double blind Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study<h4>Participants</h4>1617 men randomised to dutasteride or placebo with a prostate size >40 mL and baseline International Prostate Symptom Score (IPSS) <8. Subjects who took medications for benign prostatic hyperplasia were excluded at study entry.<h4>Interventions</h4>Placebo or dutasteride 0.5 mg daily.<h4>Main outcome measures</h4>Comparison of risk of clinical progression of benign prostatic hyperplasia at four years (defined as a ≥ 4 point worsening on IPSS, acute urinary retention, urinary tract infection, or surgery related to benign prostatic hyperplasia).<h4>Results</h4>825 participants took placebo, 792 took dutasteride. A total of 464 (29%) experienced clinical progression benign prostatic hyperplasia, 297(36%) taking placebo, 167 (21%) taking dutasteride (P<0.001). The relative risk reduction was 41% and the absolute risk reduction 15%, with a number needed to treat (NNT) of 7. Among men who had acute urinary retention and surgery related to benign prostatic hyperplasia, the absolute risk reduction for dutasteride was 6.0% and 3.8%, respectively. On multivariable regression analysis adjusting for covariates, dutasteride significantly reduced clinical progression of benign prostatic hyperplasia with an odds ratio of 0.47 (95% CI 0.37 to 0.59, P<0.001). Analysis of time to first event yielded a hazard ratio of 0.673 (P<0.001) for those taking dutasteride. Sexual adverse events were most common and similar to prior reports.<h4>Limitations</h4>Further prospective studies may be warranted to demonstrate generalisability of these results.<h4>Conclusions</h4>This study is the first to explore the benefit of treating asymptomatic or mildly symptomatic men with an enlarged prostate. Dutasteride significantly decreased the incidence of benign prostatic hyperplasia clinical progression.
Project description:We provide cross-sectional normative data on [-2]proenzyme-prostate specific antigen from the Olmsted County Study of Urinary Symptoms and Health Status among Men, and the Flint Men's Health Study. We also describe associations with clinical urological measures and the risk of prostate cancer diagnosis.Measurements of [-2]proenzyme-prostate specific antigen were obtained from 420 white men from Olmsted County, Minnesota, and 328 black men from Genesee County, Michigan. Cross-sectional associations between [-2]proenzyme-prostate specific antigen and prostate enlargement/elevated prostate specific antigen were assessed. Cox proportional hazard models were used to assess associations between [-2]proenzyme-prostate specific antigen and the incident diagnosis of prostate cancer.Baseline [-2]proenzyme-prostate specific antigen was slightly higher in black men at a median of 6.3 pg/ml (25th, 75th percentiles 4.1, 8.9) than in white men at a median of 5.6 pg/ml (25th, 75th percentiles 3.9, 7.7, respectively, p = 0.01). Baseline [-2]proenzyme-prostate specific antigen was highly predictive of biopsy confirmed prostate cancer in the Olmsted County Study cohort. Relative to men in the [-2]proenzyme-prostate specific antigen lower quartile those in the upper quartile were at almost eightfold increased risk for prostate cancer (HR 7.8, 95% CI 2.2-27.8) after adjusting for age and baseline prostate specific antigen.In these cohorts of community dwelling black and white men [-2]proenzyme-prostate specific antigen was much lower than in previous studies. These data suggest that [-2]proenzyme-prostate specific antigen may help identify prostate cancer in men with serum prostate specific antigen in an indeterminate range, although the reference ranges for white and black men may differ slightly.
Project description:Benign prostatic hyperplasia affects more than 50% of men by age 60 years, and is the cause of millions of dollars in health care expenditure for the treatment of lower urinary tract symptoms and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic benign prostatic hyperplasia. At least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5?-reductase type 2, and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of benign prostatic hyperplasia progression as well as the key genes and signaling pathways implicated in the process such as 5?-reductase. We also explore the potential of biomarker screening and gene specific therapies as tools to risk stratify patients with benign prostatic hyperplasia and identify those with symptomatic or medically resistant forms.A PubMed® literature search of current and past peer reviewed literature on prostate development, lower urinary tract symptoms, benign prostatic hyperplasia pathogenesis, targeted therapy, biomarkers, epigenetics, 5?-reductase type 2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined, as were their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications.Benign prostatic hyperplasia is associated with a state of hyperplasia of the stromal and epithelial compartments, with 5?-reductase type 2 and androgen signaling having key roles in the development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities have complex roles in prostate tissue homeostasis as well as its evolution into the clinical state of benign prostatic hyperplasia. Resistance to medical therapy with finasteride may occur through silencing of the 5?-reductase type 2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5?-reductase type 2. Novel biomarkers such as single nucleotide polymorphisms may be used to risk stratify patients with symptomatic benign prostatic hyperplasia and identify those at risk for progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate benign prostatic hyperplasia progression and may offer alternative targets for medical therapy.Progressive worsening of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia is the result of multiple pathways including androgen receptor signaling, proinflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene specific targets. As personalized medicine continues to develop, the ability to risk stratify patients with symptomatic benign prostatic hyperplasia, identify those at higher risk for progression, and seek alternative therapies for those in whom conventional options are likely to fail will become the standard of targeted therapy.
Project description:Prostate cancer and benign prostatic hyperplasia are common genitourinary diseases in aging men. Both pathologies may coexist and share numerous similarities, which have suggested several connections or some interplay between them. However, solid evidence confirming their existence is lacking. Recent studies on extensive series of prostatectomy specimens have shown that tumors originating in larger prostates present favorable pathological features. Hence, large prostates may exert a protective effect against prostate cancer. In this work, we propose a mechanical explanation for this phenomenon. The mechanical stress fields that originate as tumors enlarge have been shown to slow down their dynamics. Benign prostatic hyperplasia contributes to these mechanical stress fields, hence further restraining prostate cancer growth. We derived a tissue-scale, patient-specific mechanically coupled mathematical model to qualitatively investigate the mechanical interaction of prostate cancer and benign prostatic hyperplasia. This model was calibrated by studying the deformation caused by each disease independently. Our simulations show that a history of benign prostatic hyperplasia creates mechanical stress fields in the prostate that impede prostatic tumor growth and limit its invasiveness. The technology presented herein may assist physicians in the clinical management of benign prostate hyperplasia and prostate cancer by predicting pathological outcomes on a tissue-scale, patient-specific basis.
Project description:Prostate cancer is a highly prevalent tumor affecting millions of men worldwide, but poor understanding of its pathogenesis has limited effective clinical management of patients. In addition to transcriptional profiling or transcriptomics, metabolomics is being increasingly utilized to discover key molecular changes underlying tumorigenesis. In this study, we integrated transcriptomics and metabolomics to analyze 25 paired human prostate cancer tissues and adjacent noncancerous tissues, followed by further validation of our findings in an additional cohort of 51 prostate cancer patients and 16 benign prostatic hyperplasia patients. We found several altered pathways aberrantly expressed at both metabolic and transcriptional levels, including cysteine and methionine metabolism, nicotinamide adenine dinucleotide metabolism, and hexosamine biosynthesis. Additionally, the metabolite sphingosine demonstrated high specificity and sensitivity for distinguishing prostate cancer from benign prostatic hyperplasia, particularly for patients with low prostate specific antigen level (0-10 ng/ml). We also found impaired sphingosine-1-phosphate receptor 2 signaling, downstream of sphingosine, representing a loss of tumor suppressor gene and a potential key oncogenic pathway for therapeutic targeting. By integrating metabolomics and transcriptomics, we have provided both a broad picture of the molecular perturbations underlying prostate cancer and a preliminary study of a novel metabolic signature, which may help to discriminate prostate cancer from normal tissue and benign prostatic hyperplasia.
Project description:BACKGROUND AND PURPOSE:This study explored the association between a single-nucleotide polymorphism of prostate stem cell antigen and prostate cancer in Chinese patients undergoing prostate biopsy. MATERIALS AND METHODS:DNA from 416 patients undergoing prostate biopsy was typed for the prostate stem cell antigen rs1045531 single-nucleotide polymorphism. The frequency of the rs1045531 polymorphism in patients with prostate cancer and in patients with benign prostatic hyperplasia was compared. Associations between the polymorphism and the risk of prostate cancer, prostate special antigen, Gleason score, and clinical stage were analyzed. RESULTS:Statistically significant differences in the distribution of the rs1045531 genotypes and alleles were found between prostate cancer and benign prostatic hyperplasia in patients undergoing prostate biopsy ( P = .035 and .046, respectively). We found that the rs1045531 AC genotype was significantly associated with a high risk of prostate cancer in the heterozygote model (AC vs CC; odds ratio = 2.383, 95% confidence interval: 1.198-4.741, ?2 = 6.229, P = .013) and the dominant model (AA/AC vs CC; odds ratio = 2.169, 95% confidence interval: 1.112-4.229, ?2 = 5.228, P = .022). However, susceptibility of prostate cancer was decreased in the homozygote model (AA vs CC; odds ratio = 0.828, 95% confidence interval: 0.143-4.805, P = .601). When considering clinical factors, the rs1045531 showed an association with prostate special antigen of 10 ng/mL or greater, a Gleason score of 7 or greater, and a size of T2 or greater. CONCLUSION:Men with the rs1045531 AC genotype of prostate stem cell antigen were at higher risk of prostate cancer in Chinese patients undergoing prostate biopsy.
Project description:The incidence of benign prostatic hyperplasia increases among obese individuals, but few studies have fully explained the underlying mechanisms. Adiponectin has drawn much attention in recent years due to its protective role in obesity-related diseases. Here we aimed to investigate the possible molecular mechanisms and clinical significance of adiponectin in relation to benign prostatic hyperplasia.We analyzed data from 98 Chinese men, including 48 BPH cases and 50 controls in a case-control study. Then, we utilized a tissue microarray analysis to examine expression of AdipoR1 and p-p90RSK in normal and hyperplastic prostate tissues. These studies were followed by various in vitro approaches to examine the anti-proliferation effect and signaling pathways of adiponectin involved in benign prostatic hyperplasia.Lower serum adiponectin levels were independently associated with larger prostate volume and an increased risk of benign prostatic hyperplasia. Benign prostatic hyperplasia tissues had a decreased expression of AdipoR1 and increased expression of p-p90RSK compared with normal prostate tissues. in vitro, adiponectin inhibited the proliferation of prostatic epithelial and stromal cells and arrested cells in the G0/G1 phase by decreasing phosphorylation of the MEK-ERK-p90RSK axis.Our results suggest a possible negative regulatory mechanism in which adiponectin signaling antagonizes ERK-mediated cell proliferation, and a deficiency in adiponectin could facilitate the proliferation of prostate cells and consequently contribute to benign prostatic hyperplasia.