Search

Simple Summary: The review explores the critical role of prostate-specific membrane antigen (PSMA) PET/CT imaging in diagnosing, staging, and treating prostate cancer. PSMA PET/CT offers superior diagnostic capabilities for identifying prostate cancer's spread, with potential as a prognostic indicator for the disease's recurrence and survival. It highlights PSMA's variability in expression, impacting personalised treatment plans, notably in radioligand therapy with [177Lu] Lu-PSMA-617. This technology enhances treatment strategies, improves outcomes, and reduces unnecessary interventions, marking a significant advancement in personalised prostate cancer management. The review examines the vital role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in the diagnosis, staging, and treatment of prostate cancer (PCa). It focuses on the superior diagnostic abilities of PSMA PET/CT for identifying both nodal and distant PCa, and its potential as a prognostic indicator for biochemical recurrence and overall survival. Additionally, we focused on the variability of PSMA's expression and its impact on personalised treatment, particularly the use of [177Lu] Lu-PSMA-617 radioligand therapy. This review emphasises the essential role of PSMA PET/CT in enhancing treatment approaches, improving patient outcomes, and reducing unnecessary interventions, positioning it as a key element in personalised PCa management. [ABSTRACT FROM AUTHOR]

Abstract Background Spatial analysis can identify communities where men are at risk for aggressive prostate cancer (PCan) and need intervention. However, there are several definitions for aggressive PCan. In this study, we evaluate geospatial patterns of 3 different aggressive PCan definitions in relation to PCan-specific mortality and provide methodologic and practical insights into how each definition may affect intervention targets. Methods Using the Pennsylvania State Cancer Registry data (2005–2015), we used 3 definitions to assign “aggressive” status to patients diagnosed with PCan. Definition one (D1, recently recommended as the primary definition, given high correlation with PCan death) was based on staging criteria T4/N1/M1 or Gleason score ≥ 8. Definition two (D2, most frequently-used definition in geospatial studies) included distant SEER summary stage. Definition three (D3) included Gleason score ≥ 7 only. Using Bayesian spatial models, we identified geographic clusters of elevated odds ratios for aggressive PCan (binomial model) for each definition and compared overlap between those clusters to clusters of elevated hazard ratios for PCan-specific mortality (Cox regression). Results The number of “aggressive” PCan cases varied by definition, and influenced quantity, location, and extent/size of geographic clusters in binomial models. While spatial patterns overlapped across all three definitions, using D2 in binomial models provided results most akin to PCan-specific mortality clusters as identified through Cox regression. This approach resulted in fewer clusters for targeted intervention and less sensitive to missing data compared to definitions that rely on clinical TNM staging. Conclusions Using D2, based on distant SEER summary stage, in future research may facilitate consistency and allow for standardized comparison across geospatial studies.

Simple Summary: Active surveillance is a strategy used to manage early-stage prostate cancer without immediate treatment, aiming to maintain patients' quality of life. However, concerns remain about identifying "aggressive prostate cancer" within the active surveillance cohort, which refers to cancers with a higher potential for progression. We defined aggressive prostate cancer within the active surveillance cohort as follows: a cancer that is not an indication for active surveillance, despite low-risk or favorable intermediate-risk prostate cancer, and will undergo pathological upgrading during the course of active surveillance monitoring. The identification of aggressive prostate cancer during active surveillance is crucial, as it indicates the need for a shift in the treatment strategy. The detection of aggressive prostate cancer in these cohorts enables a timely intervention and the initiation of appropriate definitive treatment options to improve patient outcomes. To tackle this, previous studies have suggested a personalized follow-up approach that uses a mix of clinical data, biomarkers, and genetic factors to assess risk. As active surveillance indications expand, the importance of identifying aggressive prostate cancer through a personalized risk-based follow-up is expected to increase. Active surveillance has emerged as a promising approach for managing low-risk and favorable intermediate-risk prostate cancer (PC), with the aim of minimizing overtreatment and maintaining the quality of life. However, concerns remain about identifying "aggressive prostate cancer" within the active surveillance cohort, which refers to cancers with a higher potential for progression. Previous studies are predictors of aggressive PC during active surveillance. To address this, a personalized risk-based follow-up approach that integrates clinical data, biomarkers, and genetic factors using risk calculators was proposed. This approach enables an efficient risk assessment and the early detection of disease progression, minimizes unnecessary interventions, and improves patient management and outcomes. As active surveillance indications expand, the importance of identifying aggressive PC through a personalized risk-based follow-up is expected to increase. [ABSTRACT FROM AUTHOR]

Background: Spatial analysis can identify communities where men are at risk for aggressive prostate cancer (PCan) and need intervention. However, there are several definitions for aggressive PCan. In this study, we evaluate geospatial patterns of 3 different aggressive PCan definitions in relation to PCan-specific mortality and provide methodologic and practical insights into how each definition may affect intervention targets. Methods: Using the Pennsylvania State Cancer Registry data (2005–2015), we used 3 definitions to assign "aggressive" status to patients diagnosed with PCan. Definition one (D1, recently recommended as the primary definition, given high correlation with PCan death) was based on staging criteria T4/N1/M1 or Gleason score ≥ 8. Definition two (D2, most frequently-used definition in geospatial studies) included distant SEER summary stage. Definition three (D3) included Gleason score ≥ 7 only. Using Bayesian spatial models, we identified geographic clusters of elevated odds ratios for aggressive PCan (binomial model) for each definition and compared overlap between those clusters to clusters of elevated hazard ratios for PCan-specific mortality (Cox regression). Results: The number of "aggressive" PCan cases varied by definition, and influenced quantity, location, and extent/size of geographic clusters in binomial models. While spatial patterns overlapped across all three definitions, using D2 in binomial models provided results most akin to PCan-specific mortality clusters as identified through Cox regression. This approach resulted in fewer clusters for targeted intervention and less sensitive to missing data compared to definitions that rely on clinical TNM staging. Conclusions: Using D2, based on distant SEER summary stage, in future research may facilitate consistency and allow for standardized comparison across geospatial studies. [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.

The review examines the vital role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in the diagnosis, staging, and treatment of prostate cancer (PCa). It focuses on the superior diagnostic abilities of PSMA PET/CT for identifying both nodal and distant PCa, and its potential as a prognostic indicator for biochemical recurrence and overall survival. Additionally, we focused on the variability of PSMA’s expression and its impact on personalised treatment, particularly the use of [177Lu] Lu-PSMA-617 radioligand therapy. This review emphasises the essential role of PSMA PET/CT in enhancing treatment approaches, improving patient outcomes, and reducing unnecessary interventions, positioning it as a key element in personalised PCa management.

Simple Summary: Mutation in telomerase reverse transcriptase (TERT) has been reportedly related to risks of prostate cancer (PCa). However, prior genome-wide association studies (GWAS) were limited to inconsistency, small-scale, one-outcome phenotype, or single ancestry. In this study, we used two large-scale population datasets from European and Chinese ancestries to comprehensively estimate the association of TERT loci polymorphisms with prostate tumorigenesis and severity. Results of this study showed that (1) over half of the risk variants were located at the intron 2 region in both populations; (2) seven novel loci situated at intron 2, intron 6, intron 9, and intron 12 were first identified to be related to PCa risk; (3) SNPs rs2736100 and rs2853677 were significantly associated with aggressive PCa, whereas rs35812074 was marginally related to PCa death; (4) most identified loci were different between Europeans and Chinese. These findings support the evidence regarding TERT polymorphisms in relation to PCa risk and prognosis, and indicate the heterogeneous genetic architectures of PCa susceptibility loci among distinct ancestries. Background: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). Results: A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12–1.20, p = 4.12 × 10−16) and rs11291391 (OR = 1.73, 95%CI:1.34–2.25, p = 3.04 × 10−5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31–1.71, p = 2.91 × 10−9) and rs2853677 (OR = 1.74, 95%CI:1.52–1.98, p = 3.52 × 10−16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04–2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10−15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171). Conclusion: TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries. [ABSTRACT FROM AUTHOR]

Background Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer. Methods Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium. Results In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I. Conclusions These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease. [ABSTRACT FROM AUTHOR]

Germline pathogenic and likely pathogenic (P/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men and to evaluate the clinical characteristics of P/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P/LP variant in CHEK2 (4/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa. [ABSTRACT FROM AUTHOR]

Abstract Background Although prostate cancer (PCa) is the most frequent male cancer in industrialized countries, little is known about its aetiology. The literature has suggested an influence of the environment, including occupational exposures, but results are inconsistent. In this context, we investigated PCa risk associated to employment among several occupations using data from EPICAP study. Methods EPICAP is a French population-based case-control study including 819 PCa incident cases and 879 controls frequency-matched on age. In-person interviews gathered data on potential risk factors and lifetime occupational histories for each job held at least 6 months. Then, occupations were coded using ISCO 68. Unconditional logistic regressions were performed to assess the association between occupations (ever occupied and by duration) and PCa risk, whether all and aggressive, after adjusting for potential confounders. Results For ≥10 years of employment, we found positive associations with PCa, whether overall and aggressive, among Medical, Dental and Veterinary workers (OR (odds ratios) =5.01 [95% confidence interval] [1.27; 19.77]), Members of the armed forces (OR = 5.14 [0.99; 26.71]) and Fishermen, hunters and related workers (OR = 4.58 [1.33; 15.78]); whether overall and non-aggressive PCa, among Legislative officials and Government administrators (OR = 3.30 [1.10; 9.84]) or Managers (OR = 1.68 [1.18; 2.41]); however a negative association, whether overall and non-aggressive PCa, among Material-Handling and Related Equipment Operators, Dockers and Freight Handlers (OR = 0.40 [0.17; 0.97]). Conclusion Excess PCa risks were observed in the EPICAP study mostly among white collar workers exposed to several factors in their work environment. These emerging associations can be used to lead future research investigating specific occupational exposures.

Active surveillance has emerged as a promising approach for managing low-risk and favorable intermediate-risk prostate cancer (PC), with the aim of minimizing overtreatment and maintaining the quality of life. However, concerns remain about identifying “aggressive prostate cancer” within the active surveillance cohort, which refers to cancers with a higher potential for progression. Previous studies are predictors of aggressive PC during active surveillance. To address this, a personalized risk-based follow-up approach that integrates clinical data, biomarkers, and genetic factors using risk calculators was proposed. This approach enables an efficient risk assessment and the early detection of disease progression, minimizes unnecessary interventions, and improves patient management and outcomes. As active surveillance indications expand, the importance of identifying aggressive PC through a personalized risk-based follow-up is expected to increase.

Background: Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). Results: A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12–1.20, p = 4.12 × 10−16) and rs11291391 (OR = 1.73, 95%CI:1.34–2.25, p = 3.04 × 10−5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31–1.71, p = 2.91 × 10−9) and rs2853677 (OR = 1.74, 95%CI:1.52–1.98, p = 3.52 × 10−16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04–2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10−15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171). Conclusion: TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries.

Background: Although prostate cancer (PCa) is the most frequent male cancer in industrialized countries, little is known about its aetiology. The literature has suggested an influence of the environment, including occupational exposures, but results are inconsistent. In this context, we investigated PCa risk associated to employment among several occupations using data from EPICAP study. Methods: EPICAP is a French population-based case-control study including 819 PCa incident cases and 879 controls frequency-matched on age. In-person interviews gathered data on potential risk factors and lifetime occupational histories for each job held at least 6 months. Then, occupations were coded using ISCO 68. Unconditional logistic regressions were performed to assess the association between occupations (ever occupied and by duration) and PCa risk, whether all and aggressive, after adjusting for potential confounders. Results: For ≥10 years of employment, we found positive associations with PCa, whether overall and aggressive, among Medical, Dental and Veterinary workers (OR (odds ratios) =5.01 [95% confidence interval] [1.27; 19.77]), Members of the armed forces (OR = 5.14 [0.99; 26.71]) and Fishermen, hunters and related workers (OR = 4.58 [1.33; 15.78]); whether overall and non-aggressive PCa, among Legislative officials and Government administrators (OR = 3.30 [1.10; 9.84]) or Managers (OR = 1.68 [1.18; 2.41]); however a negative association, whether overall and non-aggressive PCa, among Material-Handling and Related Equipment Operators, Dockers and Freight Handlers (OR = 0.40 [0.17; 0.97]). Conclusion: Excess PCa risks were observed in the EPICAP study mostly among white collar workers exposed to several factors in their work environment. These emerging associations can be used to lead future research investigating specific occupational exposures. [ABSTRACT FROM AUTHOR]

Germline pathogenic and likely pathogenic (P/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men and to evaluate the clinical characteristics of P/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P/LP variant in CHEK2 (4/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa.

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.

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.

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.

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.

Purpose The purpose of this study was to establish the contribution of four founder alleles of NBN to prostate cancer risk and cancer survival. Materials and Methods Five thousand one hundred eighty-nine men with prostate cancer and 6,152 controls were genotyped for four recurrent variants of NBN (657del5, R215W, I171V, and E185Q). Results The NBN 657del5 mutation was detected in 74 of 5,189 unselected cases and in 35 of 6,152 controls (odds ratio [OR], 2.5; p < 0.001). In carriers of 657del5 deletion, the cancer risk was restricted to men with the GG genotype of the E185Q variant of the same gene. Among men with the GG genotype, the OR associated with 657del5 was 4.4 (95% confidence interval [CI], 2.4 to 8.0). Among men with other E185Q genotypes, the OR associated with 657del5 was 1.4 (95% CI, 0.8 to 2.4) and the interaction was significant (homogeneity p=0.006). After a median follow-up of 109 months, mortality was worse for 657del5 mutation carriers than for non-carriers (hazard ratio [HR], 1.6; p=0.001). The adverse effect of 657del5 on survival was only seen on the background of the GG genotype of E185Q (HR, 1.9; p=0.0004). Conclusion The NBN 657del5 mutation predisposes to poor prognosis prostate cancer. The pathogenicity of this mutation, with regards to both prostate cancer risk and survival, is modified by a missense variant of the same gene (E185Q). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (

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]

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]