Drug therapies for eradicating high-grade prostatic intraepithelial neoplasia in the prevention of prostate cancer

High-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor to invasive prostate cancer observed as an isolated entity in a growing subset of men undergoing prostate biopsy. The presence of HGPIN predicts an increased risk of 1) coexisting occult prostate cancer at baseline and 2) delayed progression to prostate cancer. As such, men with HGPIN represent a population at high risk for the development of prostate cancer. Because the current recommended therapy is observation and delayed-interval biopsies until cancer develops, a well-tolerated therapeutic agent capable of interrupting the progression of HGPIN to cancer is highly desirable. Given the known cancer-stimulatory effects of estrogens in the prostate, the use of selective estrogen receptor modulators (SERMs) to provide an antiestrogen effect represents a novel strategy for prostate cancer prevention. Recent phase II data from trials using toremifene in the treatment of men with HGPIN validate the use of SERMs as a rational and provocative strategy for the prevention of prostate cancer.     

Contribution of Genetic Variation rs266882 to Prostate-Specific Antigen Levels in Healthy Controls with Serum PSA Below 2.0 ng/ml

We evaluated the impact of genetic variation in the prostate-specific antigen (PSA) gene (rs266882) on serum PSA levels in healthy men as well as risk factors for benign prostate hypertrophy (BPH) and prostate cancer. The study population comprised 91 men with PSA levels below 2.0 ng/ml as healthy controls, 78 men with PSA 2–10 ng/ml as a BPH group, and 128 prostate cancer patients, all in Korea. DNA was amplified by polymerase chain reaction and the product was sequenced. We found that PSA levels were associated with a G/A polymorphism only in healthy controls. The transition, however, was not associated with PSA levels of BPH and cancer patients, nor was it a risk factor. In conclusion, this genetic factor is important for determining serum PSA levels in the naive group, whereas the disruption of prostatic architecture in BPH or prostate cancer may be a major determining factor for PSA levels.     

Oxidative DNA Damage in the Prostate May Predispose Men to a Higher Risk of Prostate Cancer

DNA damage has been associated with prostate cancer risk. Men who were referred for initial prostate biopsy for elevated prostate-specific antigen or abnormal digital rectal examination are often found with no cancer but have a higher risk of developing prostate cancer than the general population of men in their lifetime. In this study, we investigated whether DNA damage is one of the factors that predispose these men referred for prostate biopsies to a higher risk of prostate cancer. We found significantly elevated levels of 8-oxo-2-deoxyguanosine immunoreactivity in the prostates of the referred men (n = 50) in comparison to the control prostates of men (n = 32) with no indication for referral for prostate biopsy. Twelve of these control men were healthy middle-aged men and 20 of them were older men whose conditions were diagnosed with bladder cancer but with normal serum prostate-specific antigen and digital rectal examination and no evidence of prostate disease. In all the 8-oxo-2-deoxyguanosine-positive prostates, we detected phosphorylation of the ataxia telangiectasia mutated kinase and expression of the immune-stimulatory molecule MIC in the prostate epithelium. These data suggest that: 1) oxidative DNA damage has occurred in the “referred” but pathologically normal prostates, indicating that these prostates may be subjected to genomic instability and eventually neoplastic transformation; 2) in response to DNA damage, two surveillance pathways, represented by ataxia telangiectasia mutated phosphorylation and induction of the NKG2D ligand MIC, were activated to prevent tumorigenesis.     

Combination of Autoantibody Signature with PSA Level Enables a Highly Accurate Blood-Based Differentiation of Prostate Cancer Patients from Patients with Benign Prostatic Hyperplasia

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.     

A novel founder mutation in the RNASEL gene, 471delAAAG,is associated with prostate cancer in Ashkenazi Jews

HPC1/RNASEL was recently identified as a candidate gene for hereditary prostate cancer. We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews. The mutation frequency in the Ashkenazi population, estimated on the basis of the frequency in 150 healthy young women, was 4% (95% confidence interval [CI] 1.9%-8.4%). Among Ashkenazi Jews, the mutation frequency was higher in patients with prostate cancer (PRCA) than in elderly male control individuals (6.9% vs. 2.4%; odds ratio = 3.0; 95% CI 0.6-15.3; P=.17). 471delAAAG was not detected in the 134 non-Ashkenazi patients with PRCA and control individuals tested. The median age at PRCA diagnosis did not differ significantly between the Ashkenazi carriers and noncarriers included in our study. However, carriers received diagnoses at a significantly earlier age, compared with patients with PRCA who were registered in the Israeli National Cancer Registry (65 vs. 74.4 years, respectively; P<.001). When we examined two brothers with PRCA, we found a heterozygous 471delAAAG mutation in one and a homozygous mutation in the other. Loss of heterozygosity was demonstrated in the tumor of the heterozygous sib. Taken together, these data suggest that the 471delAAAG null mutation is associated with PRCA in Ashkenazi men. However, additional studies are required to determine whether this mutation confers increased risk for PRCA in this population.     

Impact of genotyping on outcome of prostatic biopsies: a multicenter prospective study

Single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk and tumor aggressiveness in retrospective studies. To assess the value of genotyping in a clinical setting, we evaluated the correlation between three genotypes (rs1447295 and rs6983267[8q24] and rs4054823[17p12]) and prostatic biopsy outcome prospectively in a French population of Caucasian men. Five hundred ninety-eight patients with prostatic-specific antigen (PSA) >4 ng/mL or abnormal digital rectal examination (DRE) participated in this prospective, multicenter study. Age, familial history of PCa, body mass index (BMI), data of DRE, International Prostate Symptom Score (I-PSS) score, PSA value and prostatic volume were collected prospectively before prostatic biopsy. Correlation between genotypes and biopsy outcome (positive or negative) and Gleason score (≤6 or >6) were studied by univariate and multivariable analysis. rs1447295 and rs6983267 risk variants were found to be associated with the presence of PCa in univariate analysis. rs6983267 genotype remained significantly linked to a positive biopsy (odds ratio [OR] = 1.66, 95% confidence interval [CI]: 1.06-2.59, P = 0.026) in multivariable analysis, but rs1447295 genotype did not (OR = 1.47, 95% CI: 0.89-2.43, P = 0.13).When biopsy outcome was stratified according to Gleason score, risk variants of rs1447295 were associated with aggressive disease (Gleason score ≥7) in univariate and multivariable analysis (OR = 2.05 95% CI: 1.10-3.79, P = 0.023). rs6983267 GG genotype was not related to aggressiveness. The results did not reach significance concerning rs4054823 for any analysis. This inaugural prospective evaluation thus confirmed potential usefulness of genotyping PCa assessment. Ongoing clinical evaluation of larger panels of SNPs will detail the actual impact of genetic markers on clinical practice.     

Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer

The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.     

Association of HPC2/ELAC2 genotypes and prostate cancer

HPC2/ELAC2 has been identified as a prostate cancer (CaP) susceptibility gene. Two common missense variants in HPC2/ELAC2 have been identified: a Ser-->Leu change at amino acid 217, and an Ala-->Thr change at amino acid 541. Tavtigian et al. reported that these variants were associated with CaP in a sample of men drawn from families with hereditary CaP. To confirm this report in a sample unselected for family history, we studied 359 incident CaP case subjects and 266 male control subjects that were frequency matched for age and race and were identified from a large health-system population. Among control subjects, the Thr541 frequency was 2.9%, and the Leu217 frequency was 31.6%, with no significant differences in frequency across racial groups. Thr541 was only observed in men who also carried Leu217. The probability of having CaP was increased in men who carried the Leu217/Thr541 variants (odds ratio = 2.37; 95% CI 1.06-5.29). This risk did not differ significantly by family history or race. Genotypes at HPC2/ELAC2 were estimated to cause 5% of CaP in the general population of inference. These results suggest that common variants at HPC2/ELAC2 are associated with CaP risk in a sample unselected for family history or other factors associated with CaP risk.     

An A/G polymorphism of core 2 branching enzyme gene is associated with prostate cancer

The expression of core 2 beta1,6-N-acetylglucosaminyltransferase-1 (C2GnT) is associated with development and progression of malignancy. Sequence analysis showed that the codon 152 of C2GnT has a polymorphism having GTT encoding valine or ATT encoding isoleucine. By examining the polymorphism in prostate cancer and benign prostatic hyperplasia patients, we found that the C2GnT G allele was more frequently observed in the prostate cancer group (p=0.015) than the control group. Men with the GG genotype had a 3.60-fold increased risk of prostate cancer, and men with the AG genotype had a 1.58-fold increased risk of prostate cancer compared with those with the AA genotype. The G allele was found to have a gene dosage effect for prostate cancer risk. No such risk was associated for benign prostatic hyperplasia. These results demonstrate that C2GnT A/G polymorphism is associated with the susceptibility to prostate cancer in a Japanese population.     

Higher Body Mass Index Increases the Risk for Biopsy-Mediated Detection of Prostate Cancer in Chinese Men

Objective

To investigate the relationship between body mass index (BMI) and prostate cancer (PCa) risk at biopsy in Chinese men.

Patients and Methods

We retrospectively reviewed the records of 1,807 consecutive men who underwent initial multicore (≥10) prostate biopsy under transrectal ultrasound guidance between Dec 2004 and Feb 2014. BMI was categorised based on the Asian classification of obesity as follows: <18.5 (underweight), 18.5–22.9 (normal weight), 23–24.9 (overweight), 25–29.9 (moderately obese), and ≥30 kg/m2 (severely obese). The odds ratios (OR) of each BMI category for risk of PCa and high-grade prostate cancer (HGPCa, Gleason score ≥4+3) detection were estimated in crude, age-adjusted and multivariate-adjusted models. Prevalence ratios and accuracies of PSA predicted PCa were also estimated across BMI groups.

Results

In total, PCa was detected by biopsy in 750 (45.4%) men, and HGPCa was detected in 419 (25.4%) men. Compared with men of normal weight, underweight men and obese men were older and had higher prostate specific antigen levels. The risk of overall PCa detection via biopsy presented an obvious U-shaped relationship with BMI in crude analysis. Overall, 50.0%, 37.4%, 45.6% 54.4% and 74.1% of the men in the underweight, normal weight, overweight, moderately obese and severely obese groups, respectively, were diagnosed with PCa via biopsy. In multivariate analysis, obesity was significantly correlated with a higher risk of PCa detection (OR = 1.17, 95%CI 1.10–1.25, P<0.001). However, higher BMI was not correlated with HGPCa detection (OR = 1.03, 95%CI 0.97–1.09, P = 0.29). There were no significant differences in the accuracy of using PSA to predict PCa or HGPCa detection across different BMI categories.

Conclusion

Obesity was associated with higher risk of PCa detection in the present Chinese biopsy population. No significant association was detected between obesity and HGPCa.     

Polymorphisms in the HPC/ELAC-2 and alpha 1-antitrypsin genes that correlate with human diseases in a North Indian population

Two genes HPC/ELAC-2 and AAT were studied in north Indian population. HPC/ELAC-2 was studied in prostate cancer cases and AAT was studied in COPD patients. HPC/ELAC-2 is considered as an important cancer-susceptibility gene in prostate cancer. There are two common polymorphisms of this gene, i.e., Ser217Leu and Ala541Thr. Alpha 1 antitrypsin is a highly polymorphic anti-elastase enzyme, especially active in the protection of alveoli and liver. In the present study, we observed the distribution of two deficient alleles PiZ and Pi S in COPD patients. We extracted the DNA from 157 prostate cancer cases, 200 COPD patients, 170 BPH and 370 healthy controls. The polymorphisms were studied by PCR–RFLP technique. The mutant genotype (Leu/Leu) of HPC/ELAC-2 was present in 9.6, 7.6 and 5.9% of BPH, cancer cases and healthy controls, respectively. Higher risk of Ser/Leu as well as Leu/Leu had shown when compared to healthy controls. That was about 1.5 and 1.7-fold (OR = 1.55; 95% CI = 0.96–2.51; OR = 1.70; 95% CI = 0.74–3.92), respectively. Risk was found to be increased in smokers and those consuming non-vegetarian diet. Our results suggest that the HPC/ELAC-2 polymorphisms, especially in localized cases, could help to predict prostate cancer risk and confirm its high prevalence of the leu/leu allele in north Indian population. Considering heterozygous PiZ genotype, we obtained an OR of 3.82 (P = 0.03). Multivariate analysis adjusted by age sex and drinking habit showed 4.15-fold increased risk for COPD in PiZ heterozygous individuals. No increased risk was observed in the individuals carrying PiS alleles.     

Manganese superoxide dismutase (MnSOD) genetic polymorphism is associated with risk of early-onset prostate cancer

Prostate cancer continues to be the most frequently diagnosed neoplasm, and the second leading cause of cancer-related mortality in men. Oxidative stress may enhance prostatic carcinogenesis. Manganese superoxide dismutase (MnSOD) is the only known superoxide scavenger in mitochondria. It plays a key role in antioxidant defense as mitochondria are important for oxidative metabolism coupled to the electron transport chain and oxidative phosphorylation and hence, ROS production. A T-->C single nucleotide substitution, resulting in a Val-->Ala change at position 9 (Ala-9Val), which alters the secondary structure of the protein, has been noted to affect transport of MnSOD into the mitochondria. We have determined the MnSOD genotype in 85 prostate cancer cases and 151 control subjects. Ala-9Val polymorphism was determined using real time polymerase chain reaction (PCR) amplification with fluorescently labeled primers. No significant difference was found in prostate cancer susceptibility in the subjects with Ala/Ala and Val/Ala genotype compared with Val/Val genotype (Odds ratio (OR), 1.3; 95% confidence interval (95% CI), 0.69-2.42; p = 0.416). We did not observe an association of the MnSOD genotype or allele frequency between subgroups of cases divided by disease status (aggressive vs. non-aggressive prostate cancer). However, in the analyses stratified by the age at diagnosis we have observed that men homozygous for Ala had a 5.2-fold increased risk of early-onset prostate cancer (under age of 65) compared to men homozygous for Val allele (p = 0.05). These data suggest that Ala/Ala MnSOD genotype in the Macedonian population could have an influence on early onset of prostate cancer, but no impact on the subsequent development of the disease.     

Poor Glycemic Control of Diabetes Mellitus Is Associated with Higher Risk of Prostate Cancer Detection in a Biopsy Population

Objectives

To evaluate the impact of glycemic control of diabetes mellitus (DM) on prostate cancer detection in a biopsy population.

Patients and Methods

We retrospectively reviewed the records of 1,368 men who underwent prostate biopsy at our institution. We divided our biopsy population into three groups according to their history of DM, and their Hemoglobin A1c (HbA1c) level: a no-DM (DM−) group; a good glycemic control (DM+GC) group (HbA1c <6.5%); and a poor glycemic control (DM+PC) group (HbA1c ≥6.5%). For sub-analyses, the DM+PC group was divided into a moderately poor glycemic control (DM+mPC) group (6.5≤ HbA1c <7.5%) and a severely poor glycemic control (DM+sPC) group (HbA1c ≥7.5%).

Results

Among 1,368 men, 338 (24.7%) had a history of DM, and 393 (28.7%) had a positive biopsy. There was a significant difference in prostatic specific antigen density (PSAD) (P = 0.037) and the frequency of abnormal DRE findings (P = 0.031) among three groups. The occurrence rate of overall prostate cancer (P<0.001) and high-grade prostate cancer (P = 0.016) also presented with a significantly difference. In the multivariate analysis, the DM+PC group was significantly associated with a higher rate of overall prostate cancer detection in biopsy subjects compared to the DM− group (OR = 2.313, P = 0.001) but the DM+PC group was not associated with a higher rate of high-grade (Gleason score ≥7) diseases detected during the biopsy (OR = 1.297, P = 0.376). However, in subgroup analysis, DM+sPC group was significantly related to a higher risk of high-grade diseases compared to the DM− group (OR = 2.446, P = 0.048).

Conclusions

Poor glycemic control of DM was associated with a higher risk of prostate cancer detection, including high-grade disease, in the biopsy population.     

Prostate-specific antigen levels among cirrhotic patients

PURPOSE: The aim of this study was to determine serum prostate-specific antigen (PSA) levels in patients with liver cirrhosis. PATIENTS AND METHODS: Between January 1995 and August 2001, 216 men with cirrhosis were evaluated. The extent of their liver disease was classified according to the Child-Pugh classification. Serum PSA levels were measured with the Hybritech Tandem-R RIA method and matched with age-related reference PSA levels. Digital rectal examination (DRE) was performed in all patients. Patients with elevated PSA levels and/or abnormal DRE were recommended to undergo further assessment including transrectal ultrasonography (TRUS) and biopsy performed by an urologist. RESULTS: Two hundred and sixteen men (mean age 54.09 +/- 9.09 years, range 25-76) with cirrhosis were examined. Their mean PSA value was 0.57 +/- 0.84 ng/mL and tended to be lower than in the normal population. The degree of PSA decrease was found to parallel the severity of the liver disease (p=0.002). The mean serum PSA level increased with each age decade in a statistically significant manner (p<0.001). Four patients (three with elevated PSA values) underwent prostate biopsy. Three biopsies were positive for prostate cancer, the other showed evidence of benign prostatic hyperplasia (BPH). CONCLUSION: Serum PSA is influenced by the severity of liver disease and its levels tend to be lower in cirrhotic patients than in the normal population. However, serum PSA can still be considered a reliable marker in the clinical management of prostatic disease in patients with cirrhosis.     

Effects of lycopene supplementation in patients with localized prostate cancer

Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.     

Variations in prostate biopsy recommendation and acceptance confound evaluation of risk factors for prostate cancer: Examining race and BMI

BackgroundProstate cancer is ubiquitous in older men; differential screening patterns and variations in biopsy recommendations and acceptance will affect which man is diagnosed and, therefore, evaluation of cancer risk factors. We describe a statistical method to reduce prostate cancer detection bias among African American (n = 3398) and Non-Hispanic White men (n = 22,673) who participated in the Selenium and Vitamin E Cancer Prevention trial (SELECT) and revisit a previously reported association between race, obesity and prostate cancer risk.MethodsFor men with screening values suggesting prostate cancer but in whom biopsy was not performed, the Prostate Cancer Prevention Trial Risk Calculator was used to estimate probability of prostate cancer. Associations of body mass index (BMI) and race with incident prostate cancer were compared for observed versus imputation-enhanced outcomes using incident density ratios.ResultsAccounting for differential biopsy assessment, the previously reported positive linear trend between BMI and prostate cancer in African American men was not observed; no BMI association was found among Non-Hispanic White men.ConclusionsDifferential disease classification among men who may be recommended to undergo and then consider whether to accept a prostate biopsy leads to inaccurate identification of prostate cancer risk factors. Imputing a man’s prostate cancer status reduces detection bias. Covariate adjustment does not address the problem of outcome misclassification. Cohorts evaluating incident prostate cancer should collect longitudinal screening and biopsy data to adjust for this potential bias.     

Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families

Prostate cancer is the most common malignancy diagnosed in men in the US. Genetic susceptibility to prostate cancer has been well documented. A region at chromosome 20q13 (HPC20) has been reported to be linked to a prostate cancer susceptibility gene. To confirm this finding, we genotyped 16 markers spanning approximately 95 cM on chromosome 20 in 159 hereditary prostate cancer (HPC) families. Positive (but not statistically significant) linkage scores were observed from 20pter to 20q11, with the highest non-parametric linkage (NPL) score for the complete dataset of 1.02 (P=0.15) being observed at D20S195 at 20q11. Evidence for linkage from parametric analyses with a dominant or a recessive model was weak. Interestingly, consistent with the original findings of linkage to 20 g higher linkage scores were observed in the subsets of families with a later age at diagnosis (> or =65 years; n=80, NPL=1.94, P=0.029 at D20S186), fewer than five affected family members (n=69, NPL=1.74, P=0.037 at D20S889), or without male-to-male disease transmission (n=60, NPL=1.01, P=0.15 at D20S117). The region with positive linkage scores spanned approximately 60 cM from 20pter to 20q11 in these subsets of families. Our results are consistent with a prostate cancer susceptibility locus on chromosome 20.     

Expression of prostate specific membrane antigen (PSMA) in prostatic adenocarcinoma and prostatic intraepithelial neoplasia

The prostatic membrane antigen (PSMA) is a protein that is expressed in the prostatic epithelium. We studied the expression of PSMA in a series of 55 patients with different stages of prostate cancer and we compared the PSMA staining in prostate cancer cells, in high-grade prostatic intraepithelial neoplasia (PIN) and in histologically benign prostatic epithelium for the same specimen. For this purpose archival paraffin-embedded specimens were studied by immunohistochemistry with a monoclonal antibody 7E11-C5.3 against PSMA using the streptavidin-biotin method. The mean percentage of PSMA immunoreactivity was 56.67% in prostate cancer (CaP) cells, and 48.6% in PIN cells, which was significantly higher than benign-appearing prostatic epithelium (5.72%) (for each pair, p<0.001). PSMA expression was greater in CaP with a higher Gleason score (p=0.01), but no relationship was found with serum PSA value. We conclude that PSMA overexpression is detected in high-grade PIN and is associated with a higher Gleason score of prostate cancer. It is a potential marker for studying carcinogenesis and progression of prostate cancer.     

In Swedish families with hereditary prostate cancer, linkage to the HPC1 locus on chromosome 1q24-25 is restricted to families with early-onset prostate cancer.

Prostate cancer clusters in some families, and an estimated 5%-10% of all cases are estimated to result from inheritance of prostate cancer-susceptibility genes. We previously reported evidence of linkage to the 1q24-25 region (HPC1) in 91 North American and Swedish families each with multiple cases of prostate cancer (Smith et al. 1996). In the present report we analyze 40 (12 original and 28 newly identified) Swedish families with hereditary prostate cancer (HPC) that, on the basis of 40 markers spanning a 25-cM interval within 1q24-25, have evidence of linkage. In the complete set of families, a maximum two-point LOD score of 1.10 was observed at D1S413 (at a recombination fraction [theta] of.1), with a maximum NPL (nonparametric linkage) Z score of 1.64 at D1S202 (P=.05). The evidence of linkage to this region originated almost exclusively from the subset of 12 early-onset (age <65 years) families, which yielded a maximum LOD score of 2.38 at D1S413 (straight theta=0) and an NPL Z score of 1.95 at D1S422 (P=.03). Estimates from heterogeneity tests suggest that, within Sweden, as many as 50% of early-onset families had evidence of linkage to the HPC1 region. These results are consistent with the hypothesis of linkage to HPC1 in a subset of families with prostate cancer, particularly those with an early age at diagnosis.     

1-Stearoylglycerol is associated with risk of prostate cancer: results from a serum metabolomic profiling analysis

Although prostate cancer is the most commonly diagnosed cancer among men in developed populations, recent recommendations against routine prostate-specific antigen screening have cast doubt on its utility for early detection. We compared the metabolomic profiles of prospectively collected fasting serum from 74 prostate cancer cases and 74 controls selected from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of male smokers. Circulating 1-stearoylglycerol (1-SG, or 1-monostearin) was statistically significantly inversely associated with risk of prostate cancer after Bonferroni correction for multiple comparisons (i.e., 420 identified metabolites) (OR 0.34, 95 % CI 0.20–0.58, p 6.3 × 10^?5). The magnitude of this association did not differ by disease aggressiveness and was observed for cases diagnosed up to 23 years after blood collection. Similar but somewhat weaker prostate cancer risk signals were also evident for glycerol and alpha-ketoglutarate. In this population, men with higher serum 1-SG were less likely to develop prostate cancer, supporting a role for dysregulation of lipid metabolism in this malignancy. Additional studies are needed to retest the association and to examine 1-SG for its potential as a prostate cancer early detection marker.