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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]

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.)

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.)