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Background: We leveraged two trials to test the hypothesis of an inflammation-prostate cancer link prospectively in men without indication for biopsy.Methods: Prostate Cancer Prevention Trial (PCPT) participants who had an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as "baseline." Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.Results: Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (N = 41) and 68.2% of controls (N = 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (N = 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum 0-

BackgroundA previous analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT) reported 82% overall prevalence of intraprostatic inflammation and identified a link between inflammation and higher-grade prostate cancer and serum PSA. Here, we studied these associations in the PCPT finasteride arm.MethodsProstate cancer cases (N = 197) detected either on a clinically indicated biopsy or on protocol-directed end-of-study biopsy, and frequency-matched controls (N = 248) with no cancer on an end-of-study biopsy were sampled from the finasteride arm. Inflammation in benign prostate tissue was visually assessed using digital images of hematoxylin and eosin-stained sections. Logistic regression was used for statistical analysis.ResultsIn the finasteride arm, 91.6% of prostate cancer cases and 92.4% of controls had at least one biopsy core with inflammation in benign areas (P < 0.001 for difference compared with placebo arm). Overall, the odds of prostate cancer did not differ by prevalence [OR, 0.90; 95% confidence interval (CI), 0.44-1.84] or extent (P trend = 0.68) of inflammation. Inflammation was not associated with higher-grade disease (prevalence: OR, 1.07; 95% CI, 0.43-2.69). Furthermore, mean PSA concentration did not differ by the prevalence or extent of inflammation in either cases or controls.ConclusionThe prevalence of intraprostatic inflammation was higher in the finasteride than placebo arm of the PCPT, with no association with higher-grade prostate cancer.ImpactFinasteride may attenuate the association between inflammation and higher-grade prostate cancer. Moreover, the missing link between intraprostatic inflammation and PSA suggests that finasteride may reduce inflammation-associated PSA elevation.

BackgroundChronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established.MethodsProstate cancer cases (N = 191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin-stained sections. Logistic regression was used to estimate associations.ResultsOf note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 [95% confidence interval (CI), 1.04-3.06] times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7-10, N = 94; OR, 2.24; 95% CI, 1.06-4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (

PurposeCyclooxygenase-2 (COX-2) is a potential pharmacologic target for the prevention of various malignancies, including prostate cancer. We conducted a randomized, double-blind trial to examine the effect of celecoxib on drug-specific biomarkers from prostate tissue obtained at prostatectomy.Patients and methodsPatients with localized prostate cancer and Gleason sum > or = 7, prostate-specific antigen (PSA) > or = 15 ng/mL, clinical stage T2b or greater, or any combination with greater than 45% risk of capsular penetration were randomly assigned to celecoxib 400 mg by mouth twice daily or placebo for 4 to 6 weeks before prostatectomy. The primary end point was the difference in prostatic prostaglandin levels between the two groups. Secondary end points were differences in COX-1 and -2 expressions; oxidized DNA bases; and markers of proliferation, apoptosis and angiogenesis. Tissue celecoxib concentrations also were measured. Tertiary end points were drug safety and compliance.ResultsSeventy-three patients consented, and 64 were randomly assigned and included in the intention-to-treat analysis. There were no treatment differences in any of the primary or secondary outcomes. Multivariable regression revealed that tumor tissue had significantly lower COX-2 expression than benign prostatic tissue (P = .01) and significantly higher levels of the proliferation marker Ki-67 (P < .0001). Celecoxib was measurable in prostate tissue of patients on treatment, demonstrating that celecoxib reached its target. Celecoxib was safe and resulted in only grade 1 toxicities.ConclusionTreatment with 4 to 6 weeks of celecoxib had no effect on intermediate biomarkers of prostate carcinogenesis, despite the achievement of measurable tissue levels. We caution against using celecoxib 400 mg twice daily as a preventive agent for prostate cancer in additional studies.

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men. [ABSTRACT FROM AUTHOR]

The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and ChIP‐seq in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on androgen receptor (AR), which is a key oncogenic driver in prostate cancer, the AR pioneer factor FOXA1, chromatin insulator CCCTC‐Binding Factor, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer, and metastatic tumor samples, signifying core AR‐driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR‐binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis‐specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome. [ABSTRACT FROM AUTHOR]

GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90–95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). In terms of association with other molecular alterations, GSTP1 positivity was enriched in ERG positive cancers among Black men. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTP1-positive tumor cells. This is the first report revealing that GSTP1-positive prostate cancers are substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men. [ABSTRACT FROM AUTHOR]

Abstract Background DNA methylation has been linked to genome regulation and dysregulation in health and disease respectively, and methods for characterizing genomic DNA methylation patterns are rapidly emerging. We have developed/refined methods for enrichment of methylated genomic fragments using the methyl-binding domain of the human MBD2 protein (MBD2-MBD) followed by analysis with high-density tiling microarrays. This MBD-chip approach was used to characterize DNA methylation patterns across all non-repetitive sequences of human chromosomes 21 and 22 at high-resolution in normal and malignant prostate cells. Results Examining this data using computational methods that were designed specifically for DNA methylation tiling array data revealed widespread methylation of both gene promoter and non-promoter regions in cancer and normal cells. In addition to identifying several novel cancer hypermethylated 5' gene upstream regions that mediated epigenetic gene silencing, we also found several hypermethylated 3' gene downstream, intragenic and intergenic regions. The hypermethylated intragenic regions were highly enriched for overlap with intron-exon boundaries, suggesting a possible role in regulation of alternative transcriptional start sites, exon usage and/or splicing. The hypermethylated intergenic regions showed significant enrichment for conservation across vertebrate species. A sampling of these newly identified promoter (ADAMTS1 and SCARF2 genes) and non-promoter (downstream or within DSCR9, C21orf57 and HLCS genes) hypermethylated regions were effective in distinguishing malignant from normal prostate tissues and/or cell lines. Conclusions Comparison of chromosome-wide DNA methylation patterns in normal and malignant prostate cells revealed significant methylation of gene-proximal and conserved intergenic sequences. Such analyses can be easily extended for genome-wide methylation analysis in health and disease.

Although Epstein-Barr virus has been detected in prostate tissue, no associations have been observed with prostate cancer in the few studies conducted to date. One possible reason for these null findings may be use of cumulative exposure measures that do not inform the timing of infection, i.e., childhood versus adolescence/early adulthood when infection is more likely to manifest as infectious mononucleosis (IM). We sought to determine the influence of young adult-onset IM on the prostate by measuring prostate-specific antigen (PSA) as a marker of prostate inflammation/damage among U.S. military members. We defined IM cases as men diagnosed with IM from 1998 to 2003 ( n = 55) and controls as men without an IM diagnosis ( n = 255). We selected two archived serum specimens for each participant, the first collected after diagnosis for cases and one randomly selected from 1998 to 2003 for controls (index), as well as the preceding specimen (preindex). PSA was measured in each specimen. To explore the specificity of our findings for prostate as opposed to systemic inflammation, we performed a post hoc comparison of other infectious disease cases without genitourinary involvement ( n = 90) and controls ( n = 220). We found that IM cases were more likely to have a large PSA rise than controls (≥20 ng/mL: 19.7% versus 8.8%, p = 0.027; ≥40% rise: 25.7% versus 9.4%, p = 0.0021), as were other infectious disease cases (25.7% versus 14.0%, p = 0.020; 27.7% versus 18.0%, p = 0.092). These findings suggest that, in addition to rising because of prostate infection, PSA may also rise because of systemic inflammation, which could have implications for PSA interpretation in older men. [ABSTRACT FROM AUTHOR]

Prostate cancer often manifests as morphologically distinct tumour foci and is frequently found adjacent to presumed precursor lesions such as high-grade prostatic intraepithelial neoplasia ( HGPIN). While there is some evidence to suggest that these lesions can be related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships between precursor lesions and invasive cancers within individual tumours remain undefined. Here, we used molecular genetic, cytogenetic, and histological analyses to delineate clonal, temporal, and spatial relationships between HGPIN and cancer lesions with distinct morphological and molecular features. First, while confirming the previous finding that a substantial fraction of HGPIN lesions associated with ERG-positive cancers share rearrangements and overexpression of ERG, we found that a significant subset of such HGPIN glands exhibit only partial positivity for ERG. This suggests that such ERG-positive HGPIN cells either rapidly invade to form adenocarcinoma or represent cancer cells that have partially invaded the ductal and acinar space in a retrograde manner. To clarify these possibilities, we used ERG expression status and TMPRSS2-ERG genomic breakpoints as markers of clonality, and PTEN deletion status to track temporal evolution of clonally related lesions. We confirmed that morphologically distinct HGPIN and nearby invasive cancer lesions are clonally related. Further, we found that a significant fraction of ERG-positive, PTEN-negative HGPIN and intraductal carcinoma ( IDC-P) lesions are most likely clonally derived from adjacent PTEN-negative adenocarcinomas, indicating that such PTEN-negative HGPIN and IDC-P lesions arise from, rather than give rise to, the nearby invasive adenocarcinoma. These data suggest that invasive adenocarcinoma can morphologically mimic HGPIN through retrograde colonization of benign glands with cancer cells. Similar clonal relationships were also seen for intraductal carcinoma adjacent to invasive adenocarcinoma. These findings represent a potentially undervalued indicator of pre-existing invasive prostate cancer and have significant implications for prostate cancer diagnosis and risk stratification. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Bone is a positive regulator of male fertility, which indicates a link between regulation of bone remodeling and reproduction or more specifically a link between calcium and androgens. This possibly suggests how calcium is linked to prostate cancer development through its link with the reproductive system. We studied serum calcium and sex steroid hormones in the Third National Health and Nutrition Examination Survey (NHANES III). Methods: Serum calcium and sex steroid hormones were measured for 1262 men in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide (AAG), and sex hormone binding globulin (SHBG) by categories of calcium (lowest 5% [<1.16 mmol/L], mid 90%, top 5% [≥1.30 mmol/L]). Results: Levels of total and free testosterone, total estradiol or AAG did not differ across categories of serum calcium. Adjusted SHBG concentrations were 36.4 for the bottom 5%, 34.2 for the mid 90% and 38.9 nmol/L for the top 5% of serum calcium ( Ptrend = 0.006), free estradiol levels were 0.88, 0.92 and 0.80 pg/ml ( Ptrend = 0.048). Conclusions: This link between calcium and sex steroid hormones, in particular the U-shaped pattern with SHBG, may, in part, explain why observational studies have found a link between serum calcium and risk of prostate cancer. [ABSTRACT FROM AUTHOR]

The heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-B]pyridine (PhIP), found in meats cooked at high temperatures, has been implicated in epidemiological and rodent studies for causing breast, prostate, and colorectal cancers. A previous animal study using a xenograft model has shown that whole tomato and broccoli, when eaten in combination, exhibit a marked effect on tumor reduction compared to when eaten alone. Our aim was to determine if PhIP-induced carcinogenesis can be prevented by dietary consumption of whole tomato + broccoli powders. Male Fischer 344 rats (n = 45) were randomized into the following treatment groups: control (AIN93G diet), PhIP (200 ppm in AIN93G diet for the first 20 weeks of the study), or tomato + broccoli + PhIP (mixed in AIN93G diet at 10% each and fed with PhIP for 20 weeks, and then without PhIP for 32 weeks). Study animals were monitored for 52 weeks and were euthanized as necessary based on a set of criteria for health status and tumor burden. Although there appeared to be some hepatic and intestinal toxicity due to the combination of PhIP and tomato + broccoli, these rodents had improved survival and reduced incidence and/or severity of PhIP-induced neoplastic lesions compared to the PhIP-alone treated group. Rats eating tomato + broccoli exhibited a marked decrease in the number and size of cribiform prostatic intraepitheilial neoplasia/carcinoma in situ (cribiform PIN/CIS) lesions and in the incidence of invasive intestinal adenocarcinomas and skin carcinomas. Although the apparent toxic effects of combined PhIP and tomato + broccoli need additional study, the results of this study support the hypothesis that a diet rich in tomato and broccoli can reduce or prevent dietary carcinogen-induced cancers. [ABSTRACT FROM AUTHOR]

TMPRSS2-ERG rearrangements occur in approximately 50% of prostate cancers and therefore represent one of the most frequently observed structural rearrangements in all cancers. However, little is known about the genomic architecture of such rearrangements. We therefore designed and optimized a pipeline involving target capture of TMPRSS2 and ERG genomic sequences coupled with paired-end next-generation sequencing to resolve genomic rearrangement breakpoints in TMPRSS2 and ERG at nucleotide resolution in a large series of primary prostate cancer specimens ( n = 83). This strategy showed > 90% sensitivity and specificity in identifying TMPRSS2-ERG rearrangements, and allowed identification of intra- and inter-chromosomal rearrangements involving TMPRSS2 and ERG with known and novel fusion partners. Our results indicate that rearrangement breakpoints show strong clustering in specific intronic regions of TMPRSS2 and ERG. The observed TMPRSS2-ERG rearrangements often exhibited complex chromosomal architecture associated with several intra- and inter-chromosomal rearrangements. Nucleotide resolution analysis of breakpoint junctions revealed that the majority of TMPRSS2 and ERG rearrangements (∼88%) occurred at or near regions of microhomology or involved insertions of one or more base pairs. This architecture implicates non-homologous end joining ( NHEJ) and microhomology-mediated end joining ( MMEJ) pathways in the generation of such rearrangements. These analyses have provided important insights into the molecular mechanisms involved in generating prostate cancer-specific recurrent rearrangements. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: DNA methylation has been linked to genome regulation and dysregulation in health and disease respectively, and methods for characterizing genomic DNA methylation patterns are rapidly emerging. We have developed/refined methods for enrichment of methylated genomic fragments using the methyl-binding domain of the human MBD2 protein (MBD2-MBD) followed by analysis with high-density tiling microarrays. This MBD-chip approach was used to characterize DNA methylation patterns across all non-repetitive sequences of human chromosomes 21 and 22 at high-resolution in normal and malignant prostate cells. Results: Examining this data using computational methods that were designed specifically for DNA methylation tiling array data revealed widespread methylation of both gene promoter and non-promoter regions in cancer and normal cells. In addition to identifying several novel cancer hypermethylated 5' gene upstream regions that mediated epigenetic gene silencing, we also found several hypermethylated 3' gene downstream, intragenic and intergenic regions. The hypermethylated intragenic regions were highly enriched for overlap with intron-exon boundaries, suggesting a possible role in regulation of alternative transcriptional start sites, exon usage and/or splicing. The hypermethylated intergenic regions showed significant enrichment for conservation across vertebrate species. A sampling of these newly identified promoter (ADAMTS1 and SCARF2 genes) and non-promoter (downstream or within DSCR9, C21orf57 and HLCS genes) hypermethylated regions were effective in distinguishing malignant from normal prostate tissues and/or cell lines. Conclusions: Comparison of chromosome-wide DNA methylation patterns in normal and malignant prostate cells revealed significant methylation of gene-proximal and conserved intergenic sequences. Such analyses can be easily extended for genome-wide methylation analysis in health and disease. [ABSTRACT FROM AUTHOR]

Many studies have shown that primary prostate cancers are multifocal and are composed of multiple genetically distinct cancer cell clones. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis and recent single-locus genetic data in prostate and other metastatic cancers, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype. [ABSTRACT FROM AUTHOR]

Purpose: We have noted that hypermethylation at GSTP1 in the preoperative serum of men with localized prostate cancer predicts early prostate specific antigen failure following surgical treatment. In this study we investigated the hypermethylation profile of several genes in the serum of men with localized and hormone refractory prostate cancer. Materials and Methods: We assayed the serum of 192 men with clinically localized prostate cancer and 18 with hormone refractory metastatic disease. A total of 35 serum samples from patients with negative prostate biopsy served as a negative control. CpG Island hypermethylation status of certain genes was assessed, including MDR1, EDNRB, CD44, NEP, PTGS2, RASSF1A, RAR-β and ESR1. The results of hypermethylation at GSTP1 were included from a previous study. Results: CpG island hypermethylation at MDR1 was positive in 38.2% of cases without PSA recurrence and in 16.1% of those with biochemical recurrence after radical prostatectomy. DNA hypermethylation at the remaining 7 gene loci was not detected in the serum of patients with localized prostate cancer. In serum from metastatic prostate cancer cases CpG island hypermethylation was detected at MDR1 in 15 (83.3%), EDNRB in 9 (50%), RAR-β in 7 (38.9%), GTSP1 in 5 (27.8%) and NEP or RASSF1A in 3 (16.7%). CpG island hypermethylation at CD44, PTGS2 or ESR was not detected in any samples. All histologically normal cases were negative for CpG island hypermethylation. Conclusions: DNA hypermethylation at MDR1 was detected in cases of localized prostate cancer. CpG island hypermethylation at several gene loci was detected in men with advanced disease. No single gene was consistently observed to be hypermethylated in men with hormone refractory disease. These results suggest that the CpG island hypermethylation status of a defined panel of genes may be a useful biomarker in men with hormone refractory prostate cancer. [Copyright &y& Elsevier]

Purpose: We evaluated the concordance between post-digital rectal examination and post-prostate biopsy urine samples using conventional methylation specific polymerase chain reaction analysis of 3 gene promoters in patients with suspected or confirmed prostate cancer. Materials and Methods: Voided urine specimens were collected from 17 men after 15-second digital rectal examination and again after transrectal ultrasound guided biopsy of the prostate for suspected malignancy or for followup biopsy as part of an expectant management protocol. Urine sediment DNA was isolated and subjected to bisulfite modification. Methylation of GSTP1, EDNRB and APC promoters was determined by conventional methylation specific polymerase chain reaction analysis in post-digital rectal examination and post-biopsy samples, and correlated with clinical information. Results: Prostate cancer was detected on prostate biopsy in 12 of 17 patients (71%). Promoter methylation was detected in post-digital rectal examination urine specimens for GSTP1 (24%), APC (12%) and EDNRB (66%). Promoter methylation was detected in post-biopsy urine specimens for GSTP1 (18%), APC (18%) and EDNRB (77%). The concordance between post-digital rectal examination and post-biopsy urine samples was 94% for GSTP1 and APC, and 82% for EDNRB. Overall 100% of patients with biopsy proven prostate cancer had at least 1 gene methylated in urine vs 60% of those without evidence of prostate cancer on biopsy. Conclusions: Gene analysis using conventional methylation specific polymerase chain reaction is a reliable method for detecting abnormal DNA methylation in voided urine samples obtained following digital rectal examination or prostate needle biopsy. The concordance between post-digital rectal examination and post-biopsy urinary samples for promoter methylation is high (82% to 94%), suggesting that urine collected after digital rectal examination may be used for genetic analysis with results similar to those in post-biopsy urine samples. [Copyright &y& Elsevier]

This review focuses on new findings and controversial issues in the the pathology and molecular biology of adenocarcinoma of the prostate. Since management of high-grade prostatic intraepithelial neoplasia on needle biopsy--the most common precursor lesion to prostate cancer--is the crucial issue with this lesion, we discuss the risk of cancer subsequent to this histological diagnosis and the issue of whether such neoplasia should be regarded as carcinoma-in-situ. We also look at prostate cancer itself, starting with its diagnosis, reporting on needle biopsy, and reviewing how the most frequently used grading system, the Gleason grading system, affects treatment. The molecular basis of prostate cancer includes inheritable and somatic genetic changes (tumour suppressor genes, loss of heterozygosity, gene targets and regions of chromosomal gain, CpG island promoter methylation, invasion and metastasis suppressor genes, telomere shortening, and genetic instability). Changed gene expression (eg, proliferation-related genes, changes in the androgen receptor, apoptosis and stress-response genes) have potential as biomarkers and therapeutic targets in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Methylation of regulatory sequences near GSTP1, which encodes the pi class glutathione S-transferase, is the most common epigenetic alteration associated with prostate cancer. We determined whether the quantitation of GSTP1 methylation in histopathologically distinct prostate tissue samples could improve prostate cancer detection.Methods: We used a fluorogenic real-time methylation-specific polymerase chain reaction (MSP) assay to analyze cytidine methylation in the GSTP1 promoter in prostate tissue samples from 69 patients with early-stage prostatic adenocarcinoma (28 of whom also had prostatic intraepithelial neoplasia lesions) and 31 patients with benign prostatic hyperplasia. The relative level of methylated GSTP1 DNA in each sample was determined as the ratio of MSP-amplified GSTP1 to MYOD1, a reference gene. We also performed a prospective, blinded investigation to quantitate GSTP1 promoter methylation in sextant prostate biopsy specimens from 21 additional patients with elevated serum prostate-specific antigen levels, 11 of whom had histologically identified adenocarcinoma and 10 of whom had no morphologic evidence of adenocarcinoma. All data were analyzed by using nonparametric two-sided statistical tests.Results: The median ratios (and interquartile ranges) of MSP-amplified GSTP1 to MYOD1 in resected benign hyperplastic prostatic tissue, intraepithelial neoplasia, and adenocarcinoma were 0 (range, 0-0.1), 1.4 (range, 0- 45.9), and 250.8 (range, 53.5-697.5), respectively; all of these values were statistically significantly different (P< .001). The median ratios of MSP-amplified GSTP1 to MYOD1 in the prospectively collected sextant biopsy samples were 410.6 for the patients with adenocarcinoma and 0.0 for the patients with no evidence of adenocarcinoma (P< .001).Conclusion: Quantitation of GSTP1 methylation accurately discriminates between normal hyperplastic tissue and prostatic carcinoma in small samples of prostate tissue and may augment the standard pathologic/histologic assessment of the prostate. [ABSTRACT FROM AUTHOR]

In this article, the author comments on a study related to prostatic cancer conducted by authors Charles Huggins and Clarence V. Hodges. Topics include correct speculation about sources of future treatment resistance, ready explanation for variations in serum acid phosphatase following orchiectomy, and documentation of a timeless and remarkable translational research.

Reports on a study conducted by researchers on prostate cancer prevention. Incidence and mortality of prostate cancer in different regions of the world; Contribution of chronic prostatitis to the development of prostate cancer; Lists of several prostate cancer prevention strategies that might help attenuate prostatic carcinogenesis.

A correction to the article "Copy Number Analysis Indicates Monoclonal Origin of Lethal Metastatic Prostate Cancer," that was published in the April 2009 is presented.

Abstract: The etiological agents that cause prostate cancer remain unknown. There is emerging evidence that “risk factor” lesions that are proposed to represent regenerative epithelium in response to environmental insults may precede the development of prostatic intraepithelial neoplasia and early carcinoma. Recent evidence suggests that these lesions, referred to collectively as proliferative inflammatory atrophy, may arise in the setting of inflammation and dietary toxins, such as “charred meat” carcinogens. Additional epidemiological, molecular pathological, and animal model work needs to be done to determine whether inflammation and atrophy are “driving” prostate carcinogenesis. [Copyright &y& Elsevier]

Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management. [ABSTRACT FROM AUTHOR]

Abstract: Context: Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. Objective: To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. Evidence acquisition: PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. Evidence synthesis: Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. Conclusions: Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic. [Copyright &y& Elsevier]

Summary: To understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland—but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance—allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation. [Copyright &y& Elsevier]

Abstract: CpG island hypermethylation may be one of the earliest somatic genome alterations to occur during the development of multiple cancers. Recently, aberrant methylation patterns for different tumors have been reported. We present a comprehensive review of the literature describing the role of CpG island hypermethlytion of DNA from prostatic tissue and bodily fluids from men with prostate cancer. We reviewed the literature to evaluate CpG island hypermethylation in tissue and bodily fluids of men with primary and metastatic prostate cancer. Additionally, we reviewed the literature with respect to CpG island hypermethylation patterns in other urological malignancies.Using modern analytic methods, CpG island hypermethylation detection can be achieved. In men with prostate cancer, correlations between specific gene regulatory region hypermethylation analyses and Gleason score, pathologic stage and tumor recurrence have been demonstrated. CpG island hypermethylation may serve as a useful molecular biomarker for the detection and diagnosis of patients with prostate cancer. [Copyright &y& Elsevier]

: ObjectivesTo evaluate the utility of methylation-specific polymerase chain reaction analysis of the pi-class glutathione-S-transferase (GSTP1) gene promoter in prostatic secretions for cancer detection and prognostication.: MethodsProstatic secretions were obtained from a total of 100 radical prostatectomy specimens immediately after surgical extirpation. GSTP1 promoter methylation was assessed by methylation-specific polymerase chain reaction analysis using two different primer sets. Correlations between GSTP1 promoter methylation and clinical and pathologic variables were examined.: ResultsThe sensitivity for detection of GSTP1 methylation in prostatic secretions from men with clinically localized prostate cancer using two different primer sets was 76% and 54%. Methylation of the GSTP1 promoter was detected by both primer sets in 44% and by at least one primer set in 86% of the prostatic secretion specimens. The degree of methylation detected in the prostatic secretions was associated with the extent of cancer (predominant involvement of one or both sides of the gland; P = 0.02) and increasing age (P = 0.009).: ConclusionsGenomic DNA with GSTP1 promoter methylation can be detected in prostatic secretion specimens from the great majority of men with localized prostate cancer. Assays of GSTP1 promoter methylation in prostatic massage fluid or ejaculate may therefore serve as useful adjuncts to existing methods for prostate cancer screening and prognostication. [Copyright &y& Elsevier]

Prostate cancer is among the most common malignancies. It is estimated that 1 in 6 men in the United States will be diagnosed with this disease. Despite the high prevalence and importance of prostate cancer, the molecular mechanisms underlying its development and progression remain poorly understood. This article reviews new information about the roles of oxidants and electrophiles in prostate cancer; the potential importance of chronic inflammation and atrophy in prostate carcinogenesis, and implications for chemoprevention; evidence supporting telomere shortening and genetic instability in the etiology of prostate cancer; and α-methylacyl-coenzyme A racemase (AMACR) as a potential marker for prostate carcinogenesis. These new results show that at least some high-grade prostatic intraepithelial neoplasias (PIN) and early adenocarcinomas appear to arise from proliferative inflammatory atrophy (PIA). Inflammation and other environmental factors may lead to the destruction of prostate epithelial cells, and increased proliferation may occur as a response to this cell death. Such proliferation may be mechanistically related to decreased p27Kip1 observed in PIA. The decreased apoptosis associated with these events may also be related to increased expression of Bcl-2. Increased oxidant and electrophile stress in the setting of increased proliferation associated with these events may lead to elevated glutathione S-transferase P1 (GSTP1) expression as a genomic-protective measure. However, aberrant methylation of the CpG island of the GSTP1 gene promoter silences GSTP1 gene expression and protein levels, setting the stage for additional genetic damage and accelerated progression toward PIN and carcinoma. Additional results show that AMACR may be an important new marker of prostate cancer, and its use in combination with p63 staining may provide the basis for an improved method for identification of prostate cancer. [Copyright &y& Elsevier]