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Objective Some studies have suggested an inverse association between acne vulgaris and the acne-related bacterium Propionibacterium acnes and prostate cancer (PCa). Self-reported acne might be an easily obtainable marker to identify men at relatively low risk of PCa and might be incorporated into PCa risk calculators. This study aimed to evaluate the association between self-reported acne and PCa in a large case-referent study. Methods and materials The case group comprised 942 patients with PCa recruited from a population-based cancer registry in 2003 to 2006, 647 of whom met the criteria for aggressive PCa. The referents ( n = 2,062) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions about acne. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using multivariable logistic regression for PCa and aggressive PCa as separate end points, while adjusting for age and family history of PCa. Results A history of acne was reported by 320 cases (33.9%) and 739 referents (35.8%). Self-reported acne was significantly associated neither with PCa (adjusted OR = 0.95, 95% CI: 0.80–1.12) nor with aggressive PCa (adjusted OR = 0.97, 95% CI: 0.80–1.18). Conclusion Self-reported acne is not suitable as a marker to identify men at low risk of aggressive PCa. [ABSTRACT FROM AUTHOR]

Aberrant protein glycosylation is known to be associated with the development of cancers. The aberrant glycans are produced by the combined actions of changed glycosylation enzymes, substrates and transporters in glycosylation synthesis pathways in cancer cells. To identify glycosylation enzymes associated with aggressive prostate cancer (PCa), we analyzed the difference in the expression of glycosyltransferase genes between aggressive and non-aggressive PCa. Three candidate genes encoding glycosyltransferases that were elevated in aggressive PCa were subsequently selected. The expression of the three candidates was then further evaluated in androgen-dependent (LNCaP) and androgen-independent (PC3) PCa cell lines. We found that the protein expression of one of the glycosyltransferases, α (1,6) fucosyltransferase (FUT8), was only detected in PC3 cells, but not in LNCaP cells. We further showed that FUT8 protein expression was elevated in metastatic PCa tissues compared to normal prostate tissues. In addition, using tissue microarrays, we found that FUT8 overexpression was statistically associated with PCa with a high Gleason score. Using PC3 and LNCaP cells as models, we found that FUT8 overexpression in LNCaP cells increased PCa cell migration, while loss of FUT8 in PC3 cells decreased cell motility. Our results suggest that FUT8 may be associated with aggressive PCa and thus is potentially useful for its prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer (PC) is one of the most frequently diagnosed cancers in males. MiR-153, as a member of the microRNA (miRNA) family, plays an important role in PC. This study aims to explore the expression and possible molecular mechanisms of the miR-153 action., Methods: Formalin-fixed paraffin-embedded (FFPE) tissues were collected from prostatectomy specimens of 29 metastatic and 32 initial stage PC patients. Expression levels of miR-153 were measured using real-time reverse transcription polymerase chain reaction (qRT-PCR). 2-ΔΔCT method was used for quantitative gene expression assessment. The candidate target genes for miR-153 were predicted by TargetScan. Mutations in target genes of miR-153 were identified using exome sequencing. Protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the potential molecular mechanisms of miR-153 in PC., Results: MiR-153 was significantly up-regulated in PC tissues compared to non-cancerous tissues. The analysis of correlation between the expression level of miR-153 and clinicopathological factors revealed a statistically significant correlation with the stage of the tumor process according to tumor, node, metastasis (TNM) staging system (p = 0.0256). ROC curve analysis was used to evaluate the predictive ability of miR-153 for metastasis development and it revealed miR-153 as a potential prognostic marker (AUC = 0.85; 95%CI 0.75-0.95; sensitivity = 0.72, specificity = 0.86)). According to logistic regression model the high expression of miR-153 increased the risk of metastasis development (odds ratios = 3.14, 95% CI 1.62-8.49; p-value = 0.006). Whole exome sequencing revealed nonsynonymous somatic mutations in collagen type IV alpha 1 (COL4A1), collagen type IV alpha 3 (COL4A3), forkhead box protein O1 (FOXO1), 2-hydroxyacyl-CoA lyase 1 (HACL1), hypoxia-inducible factor 1-alpha (HIF-1A), and nidogen 2 (NID2) genes. Moreover, KEGG analysis revealed that the extracellular matrix-receptor (ECM-receptor) interaction pathway is mainly involved in PC., Conclusion: MiR-153 is up-regulated in PC tissues and may play an important role in aggressive PC by targeting potential target genes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Because pesticides may operate through different mechanisms, the authors studied the risk of prostate cancer associated with specific pesticides in the Agricultural Health Study (1993–2007). With 1,962 incident cases, including 919 aggressive prostate cancers among 54,412 applicators, this is the largest study to date. Rate ratios and 95% confidence intervals were calculated by using Poisson regression to evaluate lifetime use of 48 pesticides and prostate cancer incidence. Three organophosphate insecticides were significantly associated with aggressive prostate cancer: fonofos (rate ratio (RR) for the highest quartile of exposure (Q4) vs. nonexposed = 1.63, 95% confidence interval (CI): 1.22, 2.17; Ptrend < 0.001); malathion (RR for Q4 vs. nonexposed = 1.43, 95% CI: 1.08, 1.88; Ptrend = 0.04); and terbufos (RR for Q4 vs. nonexposed = 1.29, 95% CI: 1.02, 1.64; Ptrend = 0.03). The organochlorine insecticide aldrin was also associated with increased risk of aggressive prostate cancer (RR for Q4 vs. nonexposed = 1.49, 95% CI: 1.03, 2.18; Ptrend = 0.02). This analysis has overcome several limitations of previous studies with the inclusion of a large number of cases with relevant exposure and detailed information on use of specific pesticides at 2 points in time. Furthermore, this is the first time specific pesticides are implicated as risk factors for aggressive prostate cancer. [ABSTRACT FROM PUBLISHER]

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Abstract: Background: Assays used for discovery of biomarkers should be robust and high-throughput, capable of analyzing a sufficiently large number of samples over a sufficiently long period of time with good precision. Methods: We evaluated the analytical performance of the Bio-Plex Pro™ Human Cancer Biomarker Panel 1, a 16-plex multiplex immunoassay, in serum for composite profiling of angiogenic factors. Because prostate cancer progression and metastasis are pathological events closely linked to angiogenesis, serum angiogenic factors are ideal candidates as prognostic biomarkers. Results: Our 5-day evaluation indicated that all 16 assays in the panel had good reproducibility (total precisions over 5 independent plates in 5days of <20%), adequate sensitivity (LOQs of majority of the assays less than 100pg/ml), and wide dynamic ranges (linearity of majority of the assays spanning across 3 logs in concentrations). Conclusions: Applying the panel to sera from prostate cancer patients with Gleason scores of 6, 7, 8–10, tumor stages that correlated with clinical outcome, we identified that the levels of sTIE-2, a soluble form of the transmembrane tyrosine kinase receptor for angiopoietins, were increased in patients with Gleason score of 8–10. Future studies are necessary to determine whether sTIE-2 could be used as a prognostic biomarker for identifying aggressive prostate cancer. [Copyright &y& Elsevier]

OBJECTIVE To study the effects of oxidative stress on prostate cancer development as the exact biological mechanisms behind the relationship remain uncertain. We previously reported a statistically significant interaction between circulating selenium levels, variants in the superoxide dismutase 2 gene ( SOD2 ; rs4880), and risk of developing prostate cancer and presenting with aggressive prostate cancer. PATIENTS AND METHODS We genotyped men with localized/regional prostate cancer for 26 loci across eight genes that are central to cellular antioxidant defence: glutathione peroxidase ( GPX1, GPX4 ), peroxisome proliferator-activated receptor γ coactivator ( PPARGC1A, PPARGC1B ), SOD1, SOD2 , and SOD3 , and 'X-ray repair complementing defective repair in Chinese hamster cell 1' ( XRCC1 ). Among 489 men, we examined the relationships between genotypes, circulating selenium levels, and risk of presenting with aggressive prostate cancer at diagnosis, as defined by stage, grade and prostate-specific antigen (PSA) level (213 aggressive cases). RESULTS Two variants in SOD2 were significantly associated with the risk of aggressive prostate cancer (rs17884057, odds ratio 0.83, 95% confidence interval 0.70-0.99; and rs4816407, 1.27, 1.02-1.57); men with A alleles at rs2842958 in SOD2 had lower plasma selenium levels (median 116 vs 121.8 μg/L, P=0.03); and the association between plasma selenium levels and risk of aggressive prostate cancer was modified by SOD1 (rs10432782) and SOD2 (rs2758330). CONCLUSION While this study was cross-sectional and these associations might be due to chance, further research is warranted on the potential important role of antioxidant defence in prostate cancer. [ABSTRACT FROM AUTHOR]

Androgens are assumed to play a central role in the pathophysiology of both prostate cancer (PC) and androgenic alopecia (AA). A correlation between the two phenotypes may be relevant for identification of men at high risk of PC. We evaluated the association between AA at different ages and PC in a large case-control study. Methods: The case group comprised 938 PC patients recruited from a population-based cancer registry. The controls (n =2160) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions on hair pattern at different ages using an adapted version of the Hamilton-Norwood scale, race and family history of PC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression. Results: Baldness at early age appeared to be associated with a lower risk of PC (baldness at age 20: OR=0.86; 95% CI 0.69–1.07 and baldness at age 40: OR=0.81; 95% CI 0.70–0.96). Baldness at completion of the questionnaire was not associated with PC: OR=1.10; 95% CI 0.89–1.34. An isolated ‘frontal baldness’ or ‘vertex baldness’ pattern was not significantly associated with PC at any age. Presence of a combined ‘frontal and vertex’ baldness pattern at age 40 was associated with a decreased risk of PC (OR=0.62; 95% CI 0.45–0.86). There were no significant associations between AA and aggressive PC. Conclusions: We did not find consistent positive associations between AA at different ages and PC. Surprisingly, if anything, baldness at early age is inversely related to PC in this study. Androgenic alopecia is not useful as an indicator of men at high risk of PC. [Copyright &y& Elsevier]

Although tobacco use has been recognized as one of the leading causes of cancer morbidity and mortality, a role of smoking in the occurrence of prostate cancer has not been established. However, evidence indicates that factors that influence the incidence of prostate cancer may differ from those that influence progression and fatality from the disease. Thus, we reviewed and summarized results from prospective cohort studies that assessed the relation between smoking and fatal prostate cancer risk, as well as epidemiological and clinical studies that focused on aggressive behavior in prostate cancer, such as poorer survival, advanced stage, or poorer differentiation at diagnosis. The majority of the prospective cohort studies showed that current smoking is associated with a moderate increase of ~30% in fatal prostate cancer risk compared to never/non-smokers. This association is likely to be an underestimate of the effect of smoking because most studies had a single assessment of smoking at baseline and long follow-up times, and the association was considerably stronger in some sub-groups of heaviest smokers, or when smoking was assessed in a relatively short period (within 10 years) prior to cancer mortality. Using aggressive behavior of prostate cancer as outcome, current smoking was associated with significantly elevated risk, ranging from around twofold to threefold or higher. Although alternative explanations, such as publication bias, residual confounding, screening bias, and the influence of smoking-related comorbidities cannot be ruled out entirely, these findings suggest that smoking is associated with aggressive behavior of prostate cancers or with a sub-group of rapidly progressing prostate cancer. Based on evidence presented in this review, cigarette smoking is likely to be a risk factor for prostate cancer progression and should be considered as a relevant exposure in prostate cancer research and prevention of mortality from this cancer. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is a heterogeneous group of tumors, including non-aggressive (NAG) and aggressive (AG) cancer, with variable clinical outcomes. Clinically, in order to assess the aggressiveness of a PCa, a core needle biopsy of a tumor is usually obtained to evaluate the Gleason pattern and score of the tumor. However, it may be difficult to assign on a small biopsy sample using histology. Therefore, additional tool is needed to aid in the assessment. We studied the diagnostic utility of 12 protein markers to identify AG tumors using immunohistochemistry (IHC) and tumor tissue microarray (TMA), including 215 cores of PCa and 111 cores of tumor-matched normal adjacent tissue (NAT). Protein markers were evaluated for their potential utility as single or combined panels for identification of AG. Of 12 proteins, PSMA, phospho-EGFR, AR and P16 were over-expressed in AG. Galectin-3, DPP4 and MAN1B1 revealed stronger staining patterns in NAG. The sensitivity and specificity of individual marker varied widely. Based on AUC values of individual marker, we constructed two- and three-marker panels. In two-marker panels, especially in the panel of DPP4 and PSMA, the AUC value reached 0.83 (ranging from 0.76 to 0.83). In three-marker panels, containing both DPP4 and PSMA with either Galectin-3 or phospho-EGFR, the AUC value reached 0.86 (ranging from 0.83 to 0.86). The specificities at 95% sensitivity of three-marker panels were also significantly improved. In addition to Gleason score, our IHC panels provide a practical tool to assess the aggressiveness of PCa., Competing Interests: None., (AJCR Copyright © 2022.)

Simple Summary: Identifying which men at the time of prostate cancer diagnosis have, or will progress to, an aggressive fatal disease will allow clinicians to assist men in making better informed treatment decisions. This will not only be important for those men whose disease is likely to remain indolent and who are currently undergoing unnecessary treatment procedures, but also for those who may need to be targeted with immediate and potentially life-saving therapy. Our case-control study confirms that men who carry BRCA1, BRCA2 and ATM germline pathogenic variants are at increased risk of aggressive disease and provides risk estimates that will be used by clinicians to improve counselling. While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The potential importance of germline genetic variation for identifying men at increased risk of prostate cancer has become increasingly recognised in recent years. We present an extensive review of the major developments in the identification of genetic loci, genes and individual variants associated with greater risk of prostate cancer, and what is currently known regarding whether these heritable prostate cancer risk factors can also inform likelihood of experiencing clinically significant rather than indolent forms of the disease. We finally discuss how these research discoveries might serve to inform clinical germline genetic testing guidelines and treatment options for prostate cancer in the future. Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine. [ABSTRACT FROM AUTHOR]

In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive (n = 11) and indolent (n = 13) on the basis of the Gleason score were collected. Tumor and adjacent normal tissue were annotated on H&E (Haemotoxylin and Eosin) slides and extracted by macro-dissection. Methylation patterns were assessed using the Illumina 850K DNA methylation platform. Raw data were processed using the Bioconductor package. Global ancestry proportions were estimated using ADMIXTURE (k = 3). One hundred eight genes including AOX1 were differentially methylated in tumor samples. Regarding the PCa aggressiveness, six hypermethylated genes (RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, and GABRQ) and 11 hypomethylated genes (COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12) were identified. Two significant differentially methylated DNA repair genes, JMJD1C and RNF169, were found. Ancestry proportion results for African, European, and Indigenous American were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation patterns related to PCa in H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort for the understanding of PCa in this population. [ABSTRACT FROM AUTHOR]

Recently, we have found that two urinary glycoproteins, prostatic acid phosphatase (ACPP) and clusterin (CLU), combined with serum prostate-specific antigen (PSA) can serve as a three-signature panel for detecting aggressive prostate cancer (PCa) based on a quantitative glycoproteomic study. To facilitate the translation of candidates into clinically applicable tests, robust and accurate targeted parallel reaction monitoring (PRM) assays that can be widely adopted in multiple labs were developed in this study. The developed PRM assays for the urinary glycopeptides, FLN*ESYK from ACPP and EDALN*ETR from CLU, demonstrated good repeatability and a sufficient working range covering three to four orders of magnitude, and their performance in differentiating aggressive PCa was assessed by the quantitative analysis of urine specimens collected from 69 nonaggressive (Gleason score = 6) and 73 aggressive (Gleason ≥ 8) PCa patients. When ACPP combined with CLU, the discrimination power was improved from an area under a curve (AUC) of 0.66 to 0.78. By combining ACPP, CLU, and serum PSA to form a three-signature panel, the AUC was further improved to 0.83 (sensitivity: 84.9%, specificity: 66.7%). Since the serum PSA test alone had an AUC of 0.68, our results demonstrated that the new urinary glycopeptide PRM assays can serve as an adjunct to the serum PSA test to achieve better predictive power toward aggressive PCa. In summary, our developed PRM assays for urinary glycopeptides were successfully applied to clinical PCa urine samples with a promising performance in aggressive PCa detection.

Background: There is an urgent need for the detection of aggressive prostate cancer. Glycoproteins play essential roles in cancer development, while urine is a noninvasive and easily obtainable biological fluid that contains secretory glycoproteins from the urogenital system. Therefore, here we aimed to identify urinary glycoproteins that are capable of differentiating aggressive from non-aggressive prostate cancer. Methods: Quantitative mass spectrometry data of glycopeptides from a discovery cohort comprised of 74 aggressive (Gleason score ≥8) and 68 non-aggressive (Gleason score = 6) prostate cancer urine specimens were acquired via a data independent acquisition approach. The glycopeptides showing distinct expression profiles in aggressive relative to non-aggressive prostate cancer were further evaluated for their performance in distinguishing the two groups either individually or in combination with others using repeated 5-fold cross validation with logistic regression to build predictive models. Predictive models showing good performance from the discovery cohort were further evaluated using a validation cohort. Results: Among the 20 candidate glycoproteins, urinary ACPP outperformed the other candidates. Urinary ACPP can also serve as an adjunct to serum PSA to further improve the discrimination power for aggressive prostate cancer (AUC= 0.82, 95% confidence interval 0.75 to 0.89). A three-signature panel including urinary ACPP, urinary CLU, and serum PSA displayed the ability to distinguish aggressive prostate cancer from non-aggressive prostate cancer with an AUC of 0.86 (95% confidence interval 0.8 to 0.92). Another three-signature panel containing urinary ACPP, urinary LOX, and serum PSA also demonstrated its ability in recognizing aggressive prostate cancer (AUC=0.82, 95% confidence interval 0.75 to 0.9). Moreover, consistent performance was observed from each panel when evaluated using a validation cohort. Conclusion: We have identified glycopeptides of urinary glycoproteins associated with aggressive prostate cancer using a quantitative mass spectrometry-based glycoproteomic approach and demonstrated their potential to serve as noninvasive urinary glycoprotein biomarkers worthy of further validation by a multi-center study., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The majority of prostate cancer (PCa) is indolent, however, a percentage of patients are initially diagnosed with metastatic disease, for which there is a worse prognosis. There is a lack of biomarkers to identify men at greater risk for developing aggressive PCa. Genome-wide association studies (GWAS) scan the genome to search associations of SNPs with specific traits, like cancer. To date, eight GWAS have resulted in the reporting of 16 SNPs associated with aggressive PCa (p < 5.00 × 10 -2 ). Still, validation studies need to be conducted to confirm the obtained results as GWAS can generate false-positive results. Furthermore, post-GWAS studies provide a better understanding of the functional consequences.

Intraductal carcinoma of the prostate (IDC-P) is a diagnostic entity characterized by architecturally or cytologically malignant-appearing prostatic glandular epithelium confined to prostatic ducts. Despite its apparent in situ nature, this lesion is associated with aggressive prostatic adenocarcinoma and is a predictor for poor prognosis when identified on biopsy or radical prostatectomy. This review discusses diagnosis, clinical features, histogenesis, and management of IDC-P, as well as current research and controversies surrounding this entity., (Copyright © 2020 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: Prostate cancer (PC) suspicion is based on prostate-specific antigen (PSA) and digital rectal examination (DRE). Multiparametric magnetic resonance imaging (mpMRI) increases prostate biopsy (PBx) specificity and sensitivity for detection of aggressive PC., Objective: To identify who benefits from mpMRI according to biopsy scenario (initial biopsy [IBx] vs repeated biopsy [RBx]) and the risk of aggressive PC according to PSA-DRE groups (G1, PSA <10ng/ml and -DRE; G2, PSA <10ng/ml and +DRE; G3, PSA ≥10ng/ml and -DRE; G4, PSA ≥10ng/ml and +DRE)., Design, Setting, and Participants: We carried out a retrospective analysis for 768 consecutive men with PC suspicion and scheduled for PBx in a referral institution in 2016 and 2017., Intervention: Pelvic 3-T mpMRI scanning, targeted biopsy (TBx) for suspicious lesions (Prostate Imaging-Reporting and Data System [PI-RADS] score >1), and 12-core systematic biopsy (SBx)., Outcome Measurements and Statistical Analysis: We measured the rate of PBx procedures that could be avoided and the rate of high-grade PC (HGPC) that would be missed among men with negative mpMRI, and the increase in HGPC detection due to TBx. Univariate and multivariate analyses were performed., Results and Limitations: The rate of avoidable biopsies (PI-RADS <3) was 24.2% overall, with 25.7% for IBx and 20.5% for RBx (p=0.057). The IBx and RBx rates were 31.2% and 19.8% in G1, 13.5% and 30.4% in G2, 23.7% and 21.9% in G3, and 2.5% and 0% in G4, respectively. The overall rate of missed HGPC was 1.0% for IBx and 6.5% for RBx (p=0.170), while the IBx and RBx rates were 1.1% and 5.2% for G1, 2.0% and 11.1% for G2, 0% and 7.7% for G3, and 0% and 0% for G4, respectively (p<0.001). The rate of HGPC (PI-RADS 3-5) diagnosed following TBx increased to 23.9% for IBx and to 32.6% for RBx overall (p<0.001), while the IBx and RBx rates were 29.0% and 45.5% for G1, 20.0% and 33.3% for G2, 40.0% and 38.9% for G3, and 0% and 0% for G4, respectively (p<0.001). Limitations are the single-institution design, the lack of randomisation, and small samples for subgroup analyses., Conclusions: mpMRI was of no benefit for men with PSA ≥10ng/ml and +DRE. Among the other men, mpMRI was of benefit in IBx and RBx as would reduce the biopsy rate by up to 25.7% and increase the net HGPC detection rate by up to 28.4%., Patient Summary: All men with suspected prostate cancer could benefit from multiparametric prostate cancer and targeted biopsy except for those with prostate-specific antigen ≥10ng/ml and positive digital rectal examination. The benefits include avoiding unnecessary prostate biopsy procedures and increasing the detection of aggressive cancer., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: MicroRNAs (miRNAs or miR-) have been linked to factors associated with aggressive prostate cancer such as biochemical recurrence and metastasis. We investigated whether circulating miRNAs in plasma could be used as diagnostic biomarkers for more aggressive prostate cancer at prostate biopsy., Methods: Men, aged 40 years and above, newly diagnosed with prostate cancer were categorized into two risk groups, low-grade (Gleason score, 6 or 7 [3 + 4] and serum prostate-specific antigen [PSA], <20 ng/mL) and high-grade (Gleason score, ≥7 (4 + 3) and serum PSA, ≥20 ng/mL) prostate cancers. The limma R package was used to compare the expression of miRNAs in plasma between the two risk groups, adjusting for age., Results: There were 66 men, aged 46-86 years, included: 40 men with low-grade and 26 men with high-grade prostate cancers. There were lower expressions of miR-28, miR-100, miR-942, and miR-28-3p, and higher expressions of miR-708, miR-1298, miR-886-3p, miR-374, miR-376c, miR-202, miR-128a, and miR-185 in high-grade compared to low-grade prostate cancer cases at biopsy, after adjusting for age (P < 0.05). These differences were no longer statistically significant after adjusting the P values for multiple comparisons., Conclusion: There was no circulating miRNA associated with high-grade prostate cancer at biopsy after adjusting for age and multiple comparisons. Nevertheless, relationships between these circulating miRNAs and high-grade prostate cancer were observed, which suggest them as promising prostate cancer biomarkers. Further investigation in a larger cohort may provide insight into their diagnostic potential for aggressive prostate cancer., (© 2019 Wiley Periodicals, Inc.)

Background: We performed profiling of the immune microenvironment of castration-resistant (CRPC) and castration-sensitive (CSPC) prostate cancer (PC) in order to identify novel targets for immunotherapy., Methods: PD-L1 and CD3/CD8 immunohistochemistry, PD-L1/2 fluorescent in situ hybridization, tumor mutation burden, microsatellite instability, and RNA-seq of 395 immune-related genes were performed in 19 CRPC and CSPC. Targeted genomic sequencing and fusion analysis were performed in 17 of these specimens., Results: CD276, PVR, and NECTIN2 were highly expressed in PC. Comparison of CRPC versus CSPC and primary versus metastatic tissue revealed the differential expression of immunostimulatory, immunosuppressive, and epithelial-to-mesenchymal transition (EMT)-related genes. Unsupervised clustering of differentially expressed genes yielded two final clusters best segregated by CRPC and CSPC status., Conclusion: CD276 and the alternative checkpoint inhibition PVR/NECTIN2/CD226/TIGIT pathway emerged as relevant to PC checkpoint inhibition target development., (© 2019 Wiley Periodicals, Inc.)

The 19q13 allele rs11672691 has been reproducibly found in association with aggressive form of prostate cancer, yet the underlying mechanism remains totally unknown. We have recently uncovered a mechanism by which rs11672691 influenced a novel oncogenic regulatory circuit, including HOXA2, PCAT19 and CEACAM21, thereby contributing to prostate cancer aggressiveness. [ABSTRACT FROM AUTHOR]

Summary Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21 , implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19 / CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic. [ABSTRACT FROM AUTHOR]

Background: DNA methylation can mimic the effects of germline mutations in cancer predisposition genes. Recently, we identified twenty-four heritable methylation marks associated with breast cancer risk. As breast and prostate cancer share genetic risk factors, including rare, high-risk mutations (eg, in BRCA2), we hypothesized that some of these heritable methylation marks might also be associated with the risk of prostate cancer., Methods: We studied 869 incident prostate cancers (430 aggressive and 439 non-aggressive) and 869 matched controls nested within a prospective cohort study. DNA methylation was measured in pre-diagnostic blood samples using the Illumina Infinium HM450K BeadChip. Conditional logistic regression models, adjusted for prostate cancer risk factors and blood cell composition, were used to estimate odds ratios and 95% confidence intervals for the association between the 24 methylation marks and the risk of prostate cancer., Results: Five methylation marks within the VTRNA2-1 promoter region (cg06536614, cg00124993, cg26328633, cg25340688, and cg26896946), and one in the body of CLGN (cg22901919) were associated with the risk of prostate cancer. In stratified analyses, the five VTRNA2-1 marks were associated with the risk of aggressive prostate cancer., Conclusions: This work highlights a potentially important new area of investigation for prostate cancer susceptibility and adds to our knowledge about shared risk factors for breast and prostate cancer., (© 2018 Wiley Periodicals, Inc.)

African American men have higher incidence rates of aggressive prostate cancer, where high levels of calcium and serum vitamin D deficient levels play a role in the racial differences in incidence. In this study, we examined associations of serum vitamin D with aggressive prostate cancer to improve our understanding of higher susceptibility of aggressive disease in this racial cohort. From Howard University Hospital, 155 African American men with clinically-identified prostate cancer were identified; 46 aggressive cases, and 58 non-aggressive cases. Serum vitamin D was assessed from fasting blood samples, and total calcium intake was assessed using the Block Food Frequency Questionnaire. Vitamin D receptor polymorphisms from three different loci were genotyped; rs731236 , rs1544410 , and rs11568820 . Multivariate logistic regression models were used to determine odds ratios (OR) and 95% confidence intervals (CI) comparing aggressive to non-aggressive prostate cancer. Vitamin D deficiency (<20 ng/mL) significantly increased risk of aggressive disease (OR: 3.1, 95% CI: 1.03-9.57, p -value = 0.04). Stratification by total calcium showed high calcium levels (≥800 mg/day) modified this association (OR: 7.3, 95% CI: 2.15-47.68, p -interaction = 0.03). Genetic variant rs11568820 appeared to increase the magnitude of association between deficient serum vitamin D and aggressive prostate cancer (OR: 3.64, 95% CI: 1.12-11.75, p -value = 0.05). These findings suggest that high incidence of aggressive prostate cancer risk in African American men may be due in-part to deficient levels of serum vitamin D. Other factors, including genetics, should be considered for future studies., Competing Interests: The authors declare no conflicts of interest.

Currently, no ideal prostate cancer (PCa) diagnostic or prognostic test is available due to the lack of biomarkers with high sensitivity and specificity. There is an unmet medical need to develop combinations of multiple biomarkers which may have higher accuracy in detection of PCa and stratification of aggressive and indolent cancer patients. The aim of this study was to test two biomarker gene panels in distinguishing PCa from benign prostate and high-risk, aggressive PCa from low-risk, indolent PCa, respectively. We identified a five-gene panel that can be used to distinguish PCa from benign prostate. The messenger RNA (mRNA) expression signature of the five genes was determined in 144 PCa and benign prostate specimens from prostatectomy. We showed that the five-gene panel distinguished PCa from benign prostate with sensitivity of 96.59 %, specificity of 92.86 %, and area under the curve (AUC) of 0.992 (p < 0.0001). The five-gene panel was further validated in a 137 specimen cohort and showed sensitivity of 84.62 %, specificity of 91.84 %, and AUC of 0.942 (p < 0.0001). To define subtypes of PCa for treatment guidance, we examined mRNA expression signature of an eight-gene panel in 87 PCa specimens from prostatectomy. The signature of the eight-gene panel was able to distinguish aggressive PCa (Gleason score >6) from indolent PCa (Gleason score ≤6) with sensitivity of 90.28 %, specificity of 80.00 %, and AUC of 0.967 (p < 0.0001). This panel was further validated in a 158 specimen cohort and showed significant difference between aggressive PCa and indolent PCa with sensitivity of 92.57 %, specificity of 70.00 %, and AUC of 0.962 (p < 0.0001). Our findings in assessing multiple biomarkers in combination may provide new tools to detect PCa and distinguish aggressive and indolent PCa for precision and personalized treatment. The two biomarker panels may be used in clinical settings for accurate PCa diagnosis and patient risk stratification for biomarker-guided treatment.

Introduction: New generations of tumor markers used to detect prostate cancer (PCa) should be able to discriminate men with aggressive PCa of those without PCa or nonaggressive tumors. The objective of this study has been to validate Prostate Health Index (PHI) as a marker of aggressive PCa in one academic institution., Methods: PHI was assessed in 357 men scheduled to prostatic biopsy between June of 2013 and July 2014 in one academic institution. Thereafter a subset of 183 men younger than 75 years and total PSA (tPSA) between 3.0 and 10.0 ng/mL, scheduled to it first prostatic biopsy, was retrospectively selected for this study. Twelve cores TRUS guided biopsy, under local anaesthesia, was performed in all cases. Total PSA, free PSA (fPSA), and [-2] proPSA (p2PSA) and prostate volume were determined before the procedure and %fPSA, PSA density (PSAd) and PHI were calculated. Aggressive tumors were considered if any Gleason 4 pattern was found. PHI was compared to %fPSA and PSAd through their ROC curves. Thresholds to detect 90%, 95% of all tumors and 95% and 100% of aggressive tumors were estimated and rates of unnecessary avoided biopsies were calculated and compared., Results: The rate of PCa detection was 37.2% (68) and the rate of aggressive tumors was 24.6% (45). The PHI area under the curve was higher than those of %fPSA and PSAd to detect any PCa (0.749 vs 0.606 and 0.668 respectively) or to detect only aggressive tumors (0.786 vs 0.677 and 0.708 respectively), however, significant differences were not found. The avoided biopsy rates to detect 95% of aggressive tumors were 20.2% for PHI, 14.8% for %fPSA, and 23.5% for PSAd. Even more, to detect all aggressive tumors these rates dropped to 4.9% for PHI, 9.3% for %fPSA, and 7.9% for PSAd., Conclusions: PHI seems a good marker to PCa diagnosis. However, PHI was not superior to %fPSA and PSAd to identify at least 95% of aggressive tumors., (Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)