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PURPOSE: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer. MATERIALS AND METHODS: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses. RESULTS: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36–1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29–2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11–1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41–1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19–5.96) and number of cancerous biopsy cores (3 vs 1–2 cores aHR 1.59, 95% CI 1.37–1.84; ≥4 vs 1–2 cores aHR 3.29, 95% CI 2.94–3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93–0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry. CONCLUSIONS: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

Summary Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC., Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.

Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤6, 7, ≥8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR=0.77; 95% CI 0.69–0.87) and high-grade disease (OR=0.77; 95% CI 0.68–0.86) in European men. Similar associations with aggressive (OR=0.72; 95% CI 0.58–0.89) and high-grade disease (OR=0.69; 95% CI 0.54–0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (

Objective To assess the frequency of a novel prostate cancer-associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology. Subjects and Methods We examined the frequency of the minor allele at rs188140481 in 4,299 North American men including 1,979 PC cases and 2,320 healthy volunteers. We compared the clinico-pathologic features of PC between carriers and non-carriers of the SNP. Results The rs188140481[A] SNP was present in 1.6% of the cohort; it was significantly more likely to be carried by men with PC than healthy controls (OR 3.14; 95% CI 1.85-5.35). After adjusting for age and PSA carriers were found 6.73-fold (95% CI 1.69-26.76) more likely to develop PC than non-carriers. Age at diagnosis, frequency of a positive family history of PC, and biochemical recurrence rates were similar between SNP carriers and non-carriers. Patients with the SNP had a proportionately higher frequency of stage ≥ T2c disease (29.5% vs. 20.1%; p = 0.13), Gleason ≥8 tumors (13.3% vs. 6.5%; p = 0.10), and extracapsular extension (28.9% vs. 18.8%; p = 0.12) compared to non-carriers. Conclusions rs188140481[A] is a rare SNP that confers greater risk of PC compared to SNPs identified by genome-wide association studies. Because of its low frequency, larger studies are needed to validate the prognostic significance of this locus, and associations with adverse pathology. Keywords: genetics, prostatic neoplasm, polymorphism, single nucleotide Introduction Prostate cancer (PC) is the most common non-skin cancer affecting men in the United States, with 238,590 new cases projected in 2013[1]. Genome-wide association (GWAS) and sequencing studies have recently generated rapid progress towards identifying genetic markers associated with increased PC risk[2]. Currently more than 77 different common single nucleotide polymorphisms (SNPs) have been identified on 11 different chromosomes that confer a modest risk of PC (OR: 1.12 - 2.04) in men of European ancestry[2-4]. The 8q24 region has emerged as a key region for PC susceptibility. In fact, it is often considered to be the genetic “hot-spot,” containing nine different PC-associated SNPs, within at least 5 distinct regions[5-9]. Recently, newer whole-genome sequencing (WGS) techniques have been used to identify rarer alleles associated with a far greater risk of developing PC and potentially more aggressive forms of the disease[10,11]. WGS has recently been employed to identify a novel SNP on 8q24 that is associated with PC in a predominantly European population[10]. This SNP was carried by only 1.1% of the men in that study. Although relatively rare, it was shown to confer a significantly greater risk of developing PC than previously identified loci (OR = 2.90). In the initial study, Gudmundsson and colleagues reported that this variant was associated with an earlier age of diagnosis (-1.26 years) and a trend toward more aggressive disease (p=0.08). Because this study focused on a cohort of European men undergoing various therapies for PC management, our objective was to further evaluate the clinical significance of this variant in a North American population, including annotated prostatectomy pathology and early follow-up for biochemical recurrence.

Objective To evaluate whether genetic correction using the genetic variants prostate-specific antigen (PSA)-single nucleotide polymorphisms (SNPs) could reduce potentially unnecessary and/or delayed biopsies in African-American men. Subjects and Methods We compared the genotypes of four PSA-SNPs between 964 Caucasian and 363 African-American men without known prostate cancer (PCa). We adjusted the PSA values based on an individual's PSA-SNP carrier status, and calculated the percentage of men that would meet commonly used PSA thresholds for biopsy (≥2.5 or ≥4.0 ng/mL) before and after genetic correction. Potentially unnecessary and delayed biopsies were defined as those men who were below and above the biopsy threshold after genetic correction, respectively. Results Overall, 349 (96.1%) and 354 (97.5%) African-American men had measured PSA levels

Genome-wide association studies have identified an increasing number of single nucleotide polymorphisms associated with prostate cancer risk. Some of these genetic variants are also associated with serum prostate specific antigen levels and lower urinary tract symptoms, raising the question of whether they are truly prostate cancer biomarkers or simply lead to detection bias. Therefore, we determined whether single nucleotide polymorphisms associated with prostate cancer risk are more strongly associated with tumor or prostate volume.The genotypes of 38 validated prostate cancer risk single nucleotide polymorphisms were determined in 1,321 white men who underwent radical prostatectomy. Univariate and multivariate analyses were performed to compare the relationship of single nucleotide polymorphism frequency with total prostate and tumor volumes.On multivariate analysis 2 single nucleotide polymorphisms on chromosome 8q24, rs16901979 (A) and rs6983267 (G), were significantly associated with increased tumor volume (p=0.01 and 0.02, respectively). In contrast, rs17632542 (T) near the PSA gene on 19q13 was associated with significantly lower tumor volume and rs10788160 (A) on 10q26 was associated with significantly larger prostate volume (p=0.02 and 0.01, respectively).Analysis of 38 single nucleotide polymorphisms associated with prostate cancer risk revealed a significant association between several on chromosome 8q24 and increased tumor volume but not prostate volume. This suggests that they are bona fide markers of prostate cancer susceptibility and possibly more aggressive disease. Other prostate cancer risk alleles are associated with prostate specific antigen and increased prostate or decreased tumor volume, suggesting detection bias due to their phenotypic influence.

Objectives: To examine temporal trends in clinico-pathological outcomes following radical prostatectomy (RP) in Ireland over time, and perform matched comparison of between Ireland and the USA based upon initiation of prostate-specific antigen (PSA) screening. Methods: Between 2000–2010, 651 RPs were carried out at a single institution in Ireland. Clinic-pathologic tumor features were compared to 1302 men treated in the USA from the same time interval (matching on year of diagnosis, 1:2 ratio). As historical comparison, we included a separate group of 150 USA men who underwent RP during the early PSA era (1990–1992). Results: We observed a downward migration in biopsy tumor burden ( p=0.002), RP tumor volume ( pConclusions: During the past decade of increasing PSA utilization in Ireland, we found evidence of pathological stage migration. In comparison to a USA population, Irish men have worse pathological characteristics, however, in comparison to the early USA PSA era, Irish men are more likely to have organ-confined disease.

Purpose: Recent studies have identified genetic variants associated with increased serum prostate specific antigen concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on prostate specific antigen, it may be possible to create a personalized prostate specific antigen cutoff to more accurately identify individuals for whom biopsy is recommended. Therefore, we determined how many men would continue to meet common biopsy criteria after genetic correction of their measured prostate specific antigen concentrations.Materials and Methods: The genotypes of 4 single nucleotide polymorphisms previously associated with serum prostate specific antigen levels (rs2736098, rs10788160, rs11067228 and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of prostate specific antigen was performed by dividing an individual's prostate specific antigen value by his combined genetic risk. Analy...

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Men fail active surveillance for a variety of reasons; however, no single reliable biomarker has been found to date which will identify these men from the outset. We know that there are about 35 prostate cancer risk alleles which have been discovered to influence risk of prostate cancer, from large-scale genome-wide association studies. Some of these have been associated with aggressive prostate cancer. Nobody has examined the potential for these risk alleles to predict men who might fail active surveillance. This study adds to the growing evidence that single nucleotide polymorphisms may be able to identify men who have aggressive prostate cancers, and that this could be part of a risk algorithm used in active surveillance protocols. OBJECTIVE • To assess whether the carrier status of 35 risk alleles for prostate cancer (CaP) is associated with having unfavourable pathological features in the radical prostatectomy specimen in men with clinically low risk CaP who fulfil commonly accepted criteria as candidates for active surveillance. PATIENTS AND METHODS • We studied men of European ancestry with CaP who fulfilled the commonly accepted clinical criteria for active surveillance (T1c, prostate-specific antigen

Contains fulltext : 172827.pdf (Publisher’s version ) (Open Access) Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 x 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 x 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 x 10(-7)).

Background Associations have been documented recently between some of the 23 single nucleotide polymorphisms newly discovered with the Collaborative Oncological Gene-environment Study iCOGS array that indicate prostate cancer (PCa) risk and aspects of disease aggressiveness. The utility of these iCOGS SNPs remains to be determined in active surveillance (AS). Objective To determine associations between iCOGS SNPs and upgrading among men who underwent surgical treatment and AS for low-risk PCa. Design, setting, and participants The genotypes of the 23 iCOGS SNPs were determined for all white subjects with biopsy Gleason score (GS) 6 including 950 men who underwent definitive treatment with surgery and 209 men who elected AS. The clinical and pathologic characteristics were documented for all subjects. Outcome measures and statistical analysis Men who underwent surgery were grouped according to their pathologic GS (upgraded was defined as GS ≥7; nonupgraded remained GS 6). Men who were enrolled in AS were also grouped according to their GS on subsequent surveillance biopsies. Statistical analyses were performed comparing the genotypes between the upgraded and nonupgraded groups. Results and limitations Overall, 31% and 34% of men were upgraded in the surgery and AS cohorts, respectively. Three iCOGS SNPs were significantly associated with the risk of upgrading in the surgical cohort. After correction for multiple testing, only rs11568818 on chromosome 11q22 remained significantly associated with upgrading. Assessment of this allele in the AS cohort reveals that it was present at noteworthy higher frequencies in men with high-grade disease on surveillance biopsies compared with nonupgraded men ( p =0.003). This study was primarily limited by the homogeneous patient population. Conclusions This is the first report of a SNP on chromosome 11q22 associated with higher grade disease in a surgical cohort that is also validated for eventual upgrading in a prospective AS cohort. Patient summary We examined the relationship between a group of genetic markers and prostate cancer (PCa) aggressiveness in a group of patients who underwent surgery for PCa and a group of patients who were enrolled in active surveillance. We found that these genetic markers helped predict which patients had more aggressive disease in both groups.

To assess the frequency of a novel prostate cancer-associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology.We examined the frequency of the minor allele at rs188140481 in 4299 North American men including 1979 men with prostate cancer and 2320 healthy volunteers. We compared the clinicopathological features of prostate cancer between carriers and non-carriers of the SNP.The rs188140481[A] SNP was present in 1.6% of the cohort; it was significantly more likely to be carried by men with prostate cancer than healthy controls (odds ratio 3.14; 95% confidence interval [CI] 1.85-5.35). After adjusting for age and PSA levels, carriers were found to be 6.73-fold (95% CI 1.69-26.76) more likely to develop prostate cancer than non-carriers. Age at diagnosis, frequency of a positive family history of prostate cancer, and biochemical recurrence rates were similar between SNP carriers and non-carriers. Patients with the SNP had a proportionately higher frequency of stage ≥T2c disease (29.5% vs 20.1%; P = 0.13), Gleason ≥8 tumours (13.3% vs 6.5%; P = 0.10), and extracapsular extension (28.9% vs 18.8%; P = 0.12) compared with non-carriers.rs188140481[A] is a rare SNP that confers greater risk of prostate cancer compared with SNPs identified by genome-wide association studies. Because of its low frequency, larger studies are needed to validate the prognostic significance of this locus, and associations with adverse pathology.

To evaluate whether genetic correction using the genetic variants prostate-specific antigen (PSA)-single nucleotide polymorphisms (SNPs) could reduce potentially unnecessary and/or delayed biopsies in African-American men.We compared the genotypes of four PSA-SNPs between 964 Caucasian and 363 African-American men without known prostate cancer (PCa). We adjusted the PSA values based on an individual's PSA-SNP carrier status, and calculated the percentage of men that would meet commonly used PSA thresholds for biopsy (≥ 2.5 or ≥ 4.0 ng/mL) before and after genetic correction. Potentially unnecessary and delayed biopsies were defined as those men who were below and above the biopsy threshold after genetic correction, respectively.Overall, 349 (96.1%) and 354 (97.5%) African-American men had measured PSA levels2.5 and4.0 ng/mL. Genetic correction in African-American men did not avoid any potentially unnecessary biopsies, but resulted in a significant (P0.001) reduction in potentially delayed biopsies by 2.5% and 3.9%, based on the biopsy threshold level.There are significant differences in the influence of the PSA-SNPs between African-American and Caucasian men without known PCa, as genetic correction resulted in an increased proportion of African-American men crossing the threshold for biopsy. These results raise the question of whether genetic differences in PSA might contribute to delayed PCa diagnosis in African-American men.

INTRODUCTION AND OBJECTIVES: Genome wide association studies have identified numerous single nucleotide polymorphisms (SNPs) that individually increase the risk of prostate cancer to a very modest extent ( 1.2-1.3 fold). Advancements in sequencing technology have enabled the identification of new genetic variants that are rare but have a much more robust association with prostate cancer susceptibility. In collaboration with deCODE Genetics, we performed whole genome sequencing and identified a new variant on chromosome 8q24 (rs18814048). We herein sought to report the association of this SNP with prostate cancer risk and associated pathologic characteristics. METHODS: A total of 4295 Caucasian men, including 1975 (46%) men with prostate cancer, were identified from a prospective prostate cancer genetic database and genotyped for rs18814048. Statistical analyses were performed to compare the frequency among cases and controls, and the relationship to pathologic tumor features at the time of radical prostatectomy. RESULTS: The mean age in the study population was 60 years with a median PSA of 5.3 ng/ml. Overall, 1.16% of men with prostate cancer were carriers for the risk allele compared to only 0.44% of healthy controls (OR 3.14, 95% CI 1.85-5.35). There was no significant difference in the proportion with a prostatectomy Gleason score 7 (OR 1.4, 95% CI 0.77-2.56, p 0.26) or non-organ confined disease (OR 1.66, 95% CI 0.86-3.22, p 0.13). CONCLUSIONS: SNP rs188140481 is a novel variant which is much less common but confers a much greater risk of prostate cancer than those previously identified through genome-wide association studies. While larger studies are required to evaluate associations with adverse pathologic features, our present results emphasize the importance of whole genome sequencing to more fully elucidate the genetics of prostate cancer susceptibility.

resent the largest prospective study of men with isolated HGPIN. The cancer detection rate on repeat biopsy in year one is higher than that reported in several smaller, retrospective studies. The current standard of care for patients with HGPIN is to monitor PSA levels and progression of HGPIN to cancer through serial prostate biopsies. This study underscores the necessity of more stringent follow-up for men with HGPIN. In addition, ERG fusion status on initial biopsy with isolated HGPIN could be of prognostic importance for PCA development and the clinicians should manage these patients accordingly.

INTRODUCTION AND OBJECTIVES: There is a clear heritable component underlying lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). Our research group recently identified 6 single nucleotide polymorphisms (SNPs) that are associated with the likelihood of severe LUTS and BPH medication use in Caucasian men. Many studies have suggested that minority populations including African-Americans (AA) are at increased risk for developing bothersome LUTS. However, the genetic predisposition for this racial disparity remains to be determined. Our objective was to determine whether a well-characterized panel of SNPs was associated with LUTS severity in AA men. METHODS: The genotypes of 38 SNPs previously associated with prostate cancer risk were determined for 620 healthy AA male volunteers. Their demographics and AUA symptom index (AUA-SI) score were documented prospectively. AUA-SI score was analyzed as a categorical (mild, moderate or severe) or continuous variable. Statistical analyses compared the frequency of the SNPs with AUA-SI score. RESULTS: Univariate analyses demonstrated that 2 SNPs including rs10934853 on chromosome 3q21 (p 0.004) and rs445114 on chromosome 8q24 (p 0.04) were inversely associated with the severity of LUTS; whereas, rs5945572 on chromosome Xp11 (p 0.09) was positively associated. After adjusting for the presence of the other genetic variants and age, rs5945572 (OR 1.33, 95% C.I. 1.04-1.71) remained significantly associated with increased urinary symptoms, while rs445114 was associated with marginally decreased urinary symptoms (OR 0.78; 95% C.I. 0.60-1.00). CONCLUSIONS: Two SNPs were associated with LUTS severity in a population of AA men. Interestingly, these same SNPs were previously associated with a well-characterized LUTS phenotype in Caucasian men. Future studies are warranted to further evaluate the genetic underpinnings for LUTS in AA men.

cohort of 434 patients with a total PSA 50 ng/mL who were referred to our institution for an initial prostate biopsy. Outpatient transrectal ultrasound-guided prostate biopsies were performed according to a standardized institutional saturation scheme (18-22 cores). Logistic regression models were fitted to test the predictors of PCa at initial biopsy. Predictive accuracy estimates of biopsy outcome predictions were quantified using the area under the receiver-operating characteristic curve (AUC). Differences in AUCs were tested using the DeLong method. Regression coefficients were used to create a nomogram that was internally validated using 200 bootstrap resamples. Finally, the extent of overestimation or underestimation of the observed PCa rate at biopsy was determined with calibration plots. RESULTS: Overall, 179 (41.2%) patients were diagnosed with PCa at initial extended prostate biopsy. In accuracy analyses, PHI emerged as the most informative independent predictor of PCa (AUC: 74.5%; p 0.001). The inclusion of PHI to a multivariable logistic regression model based on established predictors of PCa (age and digital rectal examination) significantly increased the predictive accuracy of a 3.4% extent (from 75.6 to 79.0%; p 0.001). Calibration of the nomogram was good within the whole range of predicted probabilities. CONCLUSIONS: We developed a nomogram based on PHI that can assist clinicians in the decision to biopsy by giving patients an individual risk of PCa. While internal validation provided evidences of good calibration and accuracy of the tool, external validation of our findings is still required.

INTRODUCTION AND OBJECTIVES: Following radical prostatectomy (RP) for prostate cancer (CaP), treatment success is defined by post-RP measurements of serum PSA. In most cases, conventional PSA assays (cPSA) with clinical limits of detection at 0.1 ng/mL fail to return detectable PSA values post-RP. Patients with adverse pathological features are those most in need of accurate post-RP PSA monitoring in order to rapidly identify CaP recurrence and to initiate early secondary treatment (Trock et al., JAMA 2008; 299:2760). By using a more sensitive PSA assay, the opportunity exists to measure PSA values 0.1 ng/mL in patients with adverse pathological features to expedite risk stratification. METHODS: Our study population consisted of 416 men with CaP treated by RP with conventional PSA (cPSA) values measured post-operatively. Using banked serum samples obtained at similar time points, serum PSA values were measured using a research use only nanoPSA assay (nPSA, VerisensTM PSA, Nanosphere, Inc.) that is two orders of magnitude more sensitive for PSA than the cPSA assays. In all cases, the first nPSA value following RP was used for analysis, and measured at a time point when cPSA values were undetectable. Median nPSA values were obtained for patients with favorable pathological features, adverse pathological features, and patients with CaP recurrence (cPSA 0.2 and/or secondary XRT or HT). RESULTS: The median nPSA for patients with favorable (n 90) vs adverse pathological features (n 49) was 4.4 and 2.8 pg/ml, respectively (p 0.06). The median nPSA for patients with CaP recurrence (n 21) was 28.7 pg/ml (p 0.21 vs favorable). All values are shown in the Figure. The median nPSA values were obtained for patients with the following adverse features: Gleason 8–10 (2.8 pg/ml, n 19, p 0.22 vs favorable), stage T2 (4.1 pg/ml, N 64, p 0.51 vs favorable), positive surgical margins (6.1 pg/ml, N 27, p 0.82 vs favorable), ECE (3.3 pg/ml,n 54, p 0.53 vs favorable). CONCLUSIONS: We describe the initial nPSA values measured in men with favorable and adverse pathology, and in men with CaP recurrence at early time points when the cPSA values are undetectable. Data demonstrates that the first nPSA obtained after RP correlates with CaP recurrence. The first nPSA values obtained after RP in patients with adverse pathological features, but without recurrence, are not significantly different from those with favorable pathology. This result could be due to primary treatment success in those patients with adverse pathological features who did not undergo immediate secondary treatment or demonstrate CaP recurrence. Source of Funding: Supported in part by the Urological Research Foundation, Prostate SPORE Grant (P50 CA9038605S2), the Robert H. Lurie Comprehensive Cancer Center Grant (P30 CA60553), and by the National Cancer Institute, Center of Cancer Nanotechnology Excellence (1U54 CA119341-01).

INTRODUCTION AND OBJECTIVES: Prostate Specific Antigen (PSA) is a well-documented marker for prostate cancer (CaP). PSA velocity (PSAV) is a derivative that has been used to increase PSA performance characteristics for CaP detection. Elevated PSAV may be an early sign of underlying CaP, but has somewhat limited sensitivity and specificity. Explanations for false-positive PSAV include missed CaP on biopsy; prostatitis; or assay standardization bias. Reasons for false-negative PSAV include very low volume CaP or high grade CaP (severely de-differentiated cells produce less PSA); prior, resolved prostatitis; or assay standardization bias. METHODS: We assessed patients who underwent prostate biopsy after prior screening with 3 PSA blood tests. PSAV was calculated using linear regression. Elevated PSAV was defined as change in PSA 0.35 ng/mL/yr. After stratifying based on PSAV, we specifically examined: 1) patients with an elevated PSAV but no CaP on biopsy and 2) patients with low PSAV but CaP on biopsy. RESULTS: Between 2003 and 2010, 1358 patients underwent prostate biopsy after previous screening with 3 PSA tests. 106 had PSAV 0.35 ng/mL/yr and negative biopsy. Of these, 62 (58%) had CaP on biopsy at a later date, suggesting negative biopsy at the time of elevated PSAV may have been due to missed early, low volume CaP. 10 (9.4%) biopsies revealed prostatic intraepithelial neoplasia (PIN), also suggesting a possibly missed small CaP. 12 biopsies (11.3%) had signs of prostatitis. In the remaining 22 (20.7%), cause for elevated PSAV was not readily apparent; transient inflammation, prostatic trauma, or assay standardization bias may have played a role. 480 patients with PSAV 0.35 had CaP on biopsy. Of these, 22 (4.6%) had a Gleason 8–10 tumor. 464 were treated with radical prostatectomy. Surgical pathology for 266 (55.4%) revealed total CaP volume 5% of submitted tissue. Of the remaining patients, 30% had possibly slow growing Gleason 6 tumors involving 6–20% of submitted tissue, and 54% had Gleason 7 tumors. In some cases, assay standardization bias or prior resolved prostatitis may have caused the spuriously low PSAV. CONCLUSIONS: Nearly 80% of patients with false-positive PSAV had an easily explained confounder-missed CaP or prostatitis. Nearly 60% of patients with false-positive PSAV were eventually found to have CaP, underscoring the need to closely follow a patient’s PSA despite initial negative biopsy. False-negative tests can often be explained by low volume or high Gleason grade disease, prior resolved prostatitis, or possible PSA assay standardization bias.

all regulated by high fat diet. 4 genes (GPx3, Crabp1, Cyp2b10 and Yipf5) were either up regulated and down regulated more than 2-fold in VP by the high fat diet. Although in most cases they showed the same trends, none of these genes showed statistically significant changes when DLP was analyzed by microarray analysis. In the validation, GPx3 mRNA levels were decreased by approximately 2-fold by high fat diet in not only in VP, but also in DLP and AP. In human nontransformed prostate cells (PrSC, PrEC and BPH-1), cholesterol loading decreased GPx3 expression, and increased H2O2 levels of culture medium. When GPx3 expression was reduced by a siRNA transfection, H2O2 was found to be increased in cell culture media of PrSC and BPH-1 cells, consistent with the known role of GPx3 in lowering H2O2 levels. Troglitazone increased GPx3 expression in 3 normal prostate cells, and decreased H2O2 levels. In addition, troglitazone attenuated cholesterol-induced H2O2 increase. Tissue from prostate cancer biopsies had decreased GPx3 mRNA and was inversely related to the Gleason score. CONCLUSIONS: High fat diet alters pathways related to many genes concerned with the increase of oxidative stress. GPx3, a gene identified by this analysis, was found to be down regulated by high fat diet and appears be decreased as well in human prostate cancers, suggesting that GPx3 may have a possible role in modulating carcinogenesis.

Objective To determine whether certain risk alleles are responsible for the relationship between prostate cancer (CaP) and other malignancies. CaP has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility. Methods We genotyped 1121 patients with CaP for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and their first-degree relatives. Results The most common other malignancies in the CaP probands were nonmelanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkin's lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among the probands, a significantly increased frequency of leukemia was found in the carriers of SNP rs2736098 (5p15, P = .03) and melanoma in the carriers of either SNP rs1512268 (8p21, P = .006) or SNP rs5759167 (22q13, P = .02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P = .02). The probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P = .03), and the probands with a family history of multiple myeloma and non-Hodgkin's disease were significantly more likely to be carriers of SNP rs12621278 (2q31, P = .04) and rs6465657 (7q21, P = .02), respectively. Conclusion Certain alleles associated with CaP susceptibility might be associated with an increased or a decreased risk of other malignancies in CaP probands and their first-degree relatives. Additional studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies.