Risk Of PCa Research Articles

The association of quantitative PSMA PET parameters with pathologic ISUP grade: an international multicenter analysis.

To assess if PSMA PET quantitative parameters are associated with pathologic ISUP grade group (GG) and upgrading/downgrading. PCa patients undergoing radical prostatectomy with or without pelvic lymph node dissection staged with preoperative PSMA PET at seven referral centres worldwide were evaluated. PSMA PET parameters which included SUVmax, PSMAvolume, and total PSMA accumulation (PSMAtotal) were collected. Multivariable logistic regression evaluated the association between PSMA PET quantified parameters and surgical ISUP GG. Decision-tree analysis was performed to identify discriminative thresholds for all three parameters related to the five ISUP GGs The ROC-derived AUC was used to determine whether the inclusion of PSMA quantified parameters improved the ability of multivariable models to predict ISUP GG ≥ 4. A total of 605 patients were included. Overall, 2%, 37%, 37%, 10% and 13% patients had pathologic ISUP GG1, 2, 3, 4, and 5, respectively. At multivariable analyses, all three parameters SUVmax, PSMAvolume and PSMAtotal were associated with GG ≥ 4 at surgical pathology after accounting for PSA and clinical T stage based on DRE, hospital and radioligand (all p < 0.05). Addition of all three parameters significantly improved the discrimination of clinical models in predicting GG ≥ 4 from 68% (95%CI 63 - 74) to 74% (95%CI 69 - 79) for SUVmax, 72% (95%CI 67 - 76) for PSMAvolume, 74% (70 - 79) for PSMAtotal and 75% (95%CI 71 - 80) when all parameters were included (all p < 0.05). Decision-tree analysis resulted in thresholds that discriminate between GG (SUVmax 0-6.5, 6.5-15, 15-28, > 28, PSMAvol 0-2, 2-9, 9-20 and > 20 and PSMAtotal 0-12, 12-98 and > 98). PSMAvolume was significantly associated with GG upgrading (OR 1.03 95%CI 1.01 - 1.05). In patients with biopsy GG1-3, PSMAvolume ≥ 2 was significantly associated with higher odds for upgrading to ISUP GG ≥ 4, compared to PSMAvolume < 2 (OR 6.36, 95%CI 1.47 - 27.6). Quantitative PSMA PET parameters are associated with surgical ISUP GG and upgrading. We propose clinically relevant thresholds of these parameters which can improve in PCa risk stratification in daily clinical practice.

Associations between genetically predicted concentrations of plasma proteins and the risk of prostate cancer

BackgroundProstate cancer (PCa) is a leading cause of cancer-related death in men. Understanding the proteomic landscape associated with PCa risk can provide insights into its molecular mechanisms and pave the way for potential therapeutic interventions.MethodsA proteome-wide Mendelian randomization (MR) analysis was employed to determine associations between genetically predicted protein concentrations in plasma and PCa risk. From an initial list of 4,364 proteins, significant associations were identified and validated. Multiple sensitivity analyses were also conducted to enhance the robustness of our findings.ResultsOf the 4,364 genetically predicted proteins, 308 exhibited preliminary associations with PCa risk. After rigorous statistical refinement, genetically predicted concentrations of 14 proteins showed positive associations with PCa risk, with odds ratios spanning from 1.55 (95% CI 1.28–1.87) for ATG4B to 2.67 (95% CI 1.94–3.67) for HCN1. In contrast, genetically predicted concentrations of ATG7, B2M, MSMB, and TMEM108 demonstrated inverse associations with PCa. The replication analysis further substantiated positive associations for MDH1 and LSM1, and a negative one for MSMB with PCa. A meta-analysis harmonizing primary and replication data mirrored these findings. Furthermore, the MVMR analysis pinpointed B2M and MSMB as having significant associations with PCa risk.ConclusionThe genetic evidence unveils a refined set of proteins associated with PCa risk. The findings underscore the potential of these proteins as molecular markers or therapeutic targets for PCa, calling for deeper mechanistic studies and exploration into their translational relevance.

The Prevalence of Prostate Cancer in Organ Donors With Increased Prostate-Specific Antigen

Elevated PSA levels were found in 139 kidney donors out of a total of 472 donors from our Transplant Centre tested between 2009 and 2022, representing 29,4%. We analyzed these kidney donors with elevated prostate specific antigen (PSA) levels, at mean age 47,3 years. PSA values ranged from 2.8 to 160.4 ng/ml, mean 13,9ng/ml), proper range <2.5 ng/ml. Prostate hist-pat examination was performed in 38/139 - 27% donors. 14 cases of prostate cancer (Pca) were found, Gleason 3+3 in 8 cases, 3+4 in four cases (one donor disqualification), one case Gleason 4+3 (donor disqualification), one case Gleason 4+5 (donor disqualification). There were 33 patients who met the criteria, age ≥50 years and PSA level > 10 mg/mL; of these, prostate hist-pat was performed in 24 cases, Pca was found in 10/42% cases. There were no difference between donors ≥ 50 years old, PSA>10 ng/ml with and without pathomorphological diagnosis of Pca in respect of age (mean 60,4 vs. 60,6 years), creatinine clearance according to the Cockroft-Gaulta formula (mean 101,6 vs. 94,8 ml/min) and PSA levels (mean 34,1 vs. 29,3 ng/ml). Among other donors with Pca three were <50 years with PSA >10 ng/ml and one was ≥ 50 years and PSA< 8 ng/ml. Kidneys from donors with prostate cancer were transplanted into 19 recipients, 10 men, nine women, follow-up time 1-10 years. There was no case of prostate cancer transmission. One of the recipients died of neoplasm – breast cancer. ConclusionsDonors ≥ 50 years old, PSA>10 ng/ml have higher risk of Pca. Accepting donors with Pca (Gleason 3+3, and 3+4) possesses minimal risk of transmission. All donors ≥ 50 years and also younger with increased PSA require further diagnostic procedure (e.g. DRE, USG, eventually histological examination).

Nutritional Supplement With Fermented Soy in Men With an Elevated Risk of Prostate Cancer and Negative Prostate Biopsies: General and Oncological Results From the Prospective PRAECAP Trial

Introduction & ObjectivesTo investigate the effect of a dietary supplement containing fermented soy on PSA, IPSS, changes in prostate volume and prostate cancer development after a 6-month challenge in men at increased risk of prostate cancer and negative previous biopsies. Materials & MethodsPatients with an elevated risk of PCa, defined by either 1 of the following criteria: PSA > 3 ng/ml, suspect lesion at digital rectal examination (DRE), suspect lesion at transrectal ultrasound (TRUS) / magnetic resonance imaging (MRI) and previous negative prostate biopsies (at least 8 cores) within 12 months before inclusion. Statistical analysis was carried out using a non-parametric one-sided paired Wilcoxon rank sum test, chi-square test and Fisher's exact test. ResultsIn this trial, 94 patients where eligible for analysis. A PSA response was detected in 81% of the cases. In 25.8% (24/93) of patients, a decrease of at least 3 points on the IPSS was observed. The median prostate volume did not statistically change after 6 months (p=0.908). Patients with PSA modulation required fewer investigations and had fewer positive biopsies (p<0.001) and significantly fewer ISUP≥3 lesions (p=0.02). ConclusionsWe observed a significantly lower PSA level after a 6-month challenge with a fermented soy-containing supplement, and an effect on IPSS in a subset of patients. Prescribing a fermented soy supplement in patients with an increased PCa risk could lead to a better selection of patients at real increased risk of having occult PCa.

Abstract 6146: Characterizing underlying molecular mechanisms of prostate cancer risk variants identified from multi-ethnic GWAS

Abstract Prostate cancer (PCa) is a complex disease with the second leading cause of cancer death in US males. Multi-ethnic genome-wide association studies (GWAS) identified a thousand genetic variants associated with PCa risk in different races. However, the majority of risk variants are located in non-coding regions, making it challenging to understand their contribution to PCa risk. Non-coding regions include functional regulatory elements (REs) such as promoters and enhancers, whose activity can be evaluated by histone modification H3K4me3 and H3K27ac, respectively. In this study, we integrated PCa risk variants with hundreds of H3K4me3 and H3K27ac ChIP-seq data from normal and cancer prostate cell lines and tissues, finding 122 variants in promoters and 301 variants in enhancers. Enhancers are distal to promoters, and they form loops to regulate gene expression, mediated by transcription factors (TFs). Enhancer activities are tightly associated with cell fate. Genetic variants can affect the activity of enhancers by changing the binding preference of TFs and such changes can affect chromatin interactions and dysregulate gene expression. We hypothesize that allele changes of enhancer variants contribute to PCa risk differently among individuals from different ancestries, leading to the development of heterogeneous PCa molecular subgroups, characterized by genetic alterations including TMPRSS2-ERG fusion. By integrating H3K27ac ChIP-seq data from prostate cell lines derived from European (EUR) and African (AFR) ancestries, we found 185 risk variants in enhancers in EUR cell lines and 69 risk variants in enhancers in AFR cell lines. Next, we integrated patient tissue-derived H3K27ac ChIP-seq data and performed chromatin quantitative trait loci (cQTL) and allelic imbalance (AI) analyses to determine risk variants associated with enhancer activity. Among the 185 risk enhancer variants in EUR and 69 in AFR cell lines, we found 130 and 46 with significant association, respectively. To determine TFs that change binding upon allele change of enhancer risk variants, we integrated hundreds of TF ChIP-seq data from prostate cell lines and tissues. Among the 185 risk enhancer variants in EUR and 69 in AFR cell lines, we found 142 and 44 variants bound by TFs, respectively. When we further performed cQTL and AI analyses for FOXA1, HOXB13, and AR, we found 87 and 29 variants significantly associated with TF binding affinity, respectively. Moreover, we found that these associations differ between TMPRSS2-ERG fusion positive and negative tumors. To identify the target genes of enhancer risk variants, we are currently integrating chromatin interaction data including Hi-C and Micro-C. Overall, this study provides valuable insights into the underlying molecular mechanisms of risk variants in various populations and individuals which lead to the development of heterogeneous PCa subgroups. Citation Format: Zexun Wu, Andrew Vu, Ethan S. Nelson-Moore, Huan Cao, Suhn K. Rhie. Characterizing underlying molecular mechanisms of prostate cancer risk variants identified from multi-ethnic GWAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6146.

Abstract 2975: Vitamin D receptor signaling limits DNA damage at early stage of prostate tumorigenesis and prevents tumor aggressiveness

Abstract Prostate cancer (PCa) is the most common visceral neoplasm and the second leading cause of cancer-related deaths in male of western societies. Low circulating vitamin D levels and reduced expression of its receptor (VDR) correlate with PCa risk and severity, but the clinical use of vitamin D is limited by its pro-calcemic activities. To characterize the role of VDR in PCa, PTEN(i)pe-/− mice, that recapitulate the human disease and in which the tumor suppressor gene PTEN is selectively inactivated in prostatic epithelial cells (PECs) at adulthood, were compared to PTEN/VDR(i)pe-/− mice in which PECs are PTEN and VDR-deficient. Histological analysis showed that prostatic intraepithelial neoplasia (PIN) are formed between 1-3 months after gene inactivation (AGI). Importantly, VDR-deficiency increased by 2-fold the PECs proliferation rate as early as 1-month AGI. At this stage, RNA-seq and immunohistochemistry analysis revealed the presence of oxidative DNA damage selectively in VDR-deficient PINs. Moreover, a 4-week supplementation with the antioxidant N-acetyl cysteine reduced oxidative DNA damage in PTEN/VDR(i)pe-/- prostates, and normalized the number of Ki-67+ cells to the levels of PTEN(i)pe-/- ones. After 3 months AGI, both PTEN(i)pe-/- and PTEN/VDR(i)pe-/- tumors entered in a latency phase characterized by cellular senescence. However, the prostate weight in PTEN/VDR(i)pe-/− mice was 2-fold higher than in PTEN(i)pe-/− mice 12 months AGI. In addition, tumors of PTEN(i)pe-/− were mostly composed of non-invasive PIN-like adenocarcinoma, whereas invasive adenocarcinoma, sarcomatoid and squamous-cell carcinoma were observed in those of PTEN/VDR(i)pe-/- mice. Using single cell and spatial transcriptomics, we unraveled the presence of epithelial cells with epithelial-mesenchymal transition (EMT) hallmarks in PTEN/VDR(i)pe-/− prostate 10 months AGI. In addition, immunophenotyping revealed a higher infiltration of neutrophils, also termed as myeloid-derived suppressive cells and implicated in EMT and metastasis dissemination, in PTEN/VDR(i)pe-/− prostates compared to PTEN(i)pe-/− ones. Moreover, pan-cytokeratin-positive micro-metastasis were detected in lymph nodes and livers of PTEN/VDR(i)pe-/− mice, but not in those of PTEN(i)pe-/- mice, demonstrating that VDR-deficiency in PECs promotes aggressive PCa. Thus, VDR signaling exerts a protective role on PTEN-deficient PECs by limiting the oxidative-stress and proliferation during PINs initiation, and prevents PCa progression. Citation Format: Kateryna Len, Justine Gantzer, Nicolas Le May, Christelle Thibault-Carpentier, Daniel Metzger, Gilles Laverny. Vitamin D receptor signaling limits DNA damage at early stage of prostate tumorigenesis and prevents tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2975.

Abstract 6143: Association of polygenic risk score and prostate tumor biomarkers with lethal prostate cancer

Abstract Prostate cancer (PCa) is a highly heritable cancer. While polygenic risk scores (PRS) stratify overall PCa risk among cancer-free men, they have not been reported to predict lethal outcomes in PCa patients. We aimed to examine to what extent PRS modifies associations between tumor biomarkers with cancer prognosis after diagnosis. We included men with primary, non-metastatic PCa in the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The PRS was constructed with 451 risk variants identified from prior PCa GWAS, measured on DNA from blood or buccal, standardized by adjusting for mean and standard deviation (SD) based on men without PCa with array-based genotyping data in HPFS/PHS. Prostate tumor biomarkers of molecular subtypes (TMPRSS2:ERG fusion, PTEN loss, and TP53 missense mutations from validated immunohistochemistry assays), insulin/lipid signaling pathways (FASN, IR, and IGF1-R), and cellular proliferation and tumor microenvironment (Ki-67, apoptosis rates, and angiogenesis) were measured on tumor tissue from radical prostatectomy or TURMP. Sample sizes varied by tumor biomarkers, ranging from 214 for angiogenesis markers to 598 for ERG protein expression. We first used either logistic or negative binomial regression to evaluate the association between the PRS and the protein expression (levels) of each individual biomarker, and then evaluated the addition of multiplicative interaction terms between PRS and biomarkers to logistic regression models for lethal PCa, defined as metastases or death from PCa. Lastly, we evaluated the predictive performance for lethal PCa by area under the curve (AUC). All models adjusted for age at diagnosis and Gleason score. Among all patients included in the analysis, the median age at diagnosis was 66 (interquartile range: 62-70) years, with 20% having a Gleason score≥8 and 10% having lethal PCa. PRS showed no association with lethal PCa (OR per SD increase PRS=0.95, 95%CI 0.85-1.06) or most tumor biomarkers, except for the apoptosis index (per SD in PRS corresponding to 0.22 units increase, 95%CI 0.02-0.42). Statistically significant interactions were found between PRS and p53 overexpression (p interaction = 1.6x10-5), PTEN loss (p=3.7x10-3), FASN (p=0.03), and Ki-67 (p=1.6x10-3), suggesting that compared to men with a PRS higher than the median, TP53 missense mutation, PTEN loss, higher FASN intensity, and higher Ki-67 indices were more strongly associated with lethal PCa in patients with lower PRS. Incorporating PRS with tumor biomarkers into predictive models enhanced the AUC beyond a model with tumor biomarker and age. The largest improvements were observed when combining the PRS with Ki-67 and apoptosis, showing absolute increases of 5% and 7% respectively. In conclusion, PRS integration with tumor biomarkers at diagnosis potentially improves the prediction of lethal PCa, thereby informing more targeted management strategies. Citation Format: Anqi Wang, Anna Plym, Konrad H. Stopsack, Lorelei A. Mucci, Kathryn L. Penney. Association of polygenic risk score and prostate tumor biomarkers with lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6143.

Genetic association of lipid-lowering drug target genes with erectile dysfunction and male reproductive health.

The effect of hypolipidemic drugs on male erectile function is still controversial. This Mendelian randomization (MR) study aimed to explore the potential impact of lipid-lowering drug targets on ED. We collected seven genetic variants encoding lipid-lowering drug targets (LDLR, HMGCR, NPC1L1, PCSK9, APOB, APOC3 and LPL) from published genome-wide association study (GWAS) statistics, and performed drug target MR analysis. The risk of ED was defined as the primary outcome, sex hormone levels and other diseases as the secondary outcomes. Mediation analyses were performed to explore potential mediating factors. The results showed that LDLR, LPL agonists and APOC3 inhibitors were significantly associated with a reduced risk of ED occurrence. APOB inhibitors were associated with an increased risk of ED occurrence. In terms of sex hormone levels, LDLR and LPL agonists were significantly associated with increased TT levels, and HMGCR was associated with decreased TT and BT levels significantly. In terms of male-related disease, MR results showed that LDLR agonists and PCSK9 inhibitors were significantly associated with an elevated risk of PH; HMGCR, NPC1L1 inhibitors were associated with a reduced risk of PCa; and LDLR agonists were significantly associated with a reduced risk of AS and MI; in addition, HMGCR inhibitors were associated with a reduced risk of PCa. After performing drug-targeted MR analysis, we found that that there was a causal relationship between lipid-lowering drug targets and ED. APOC3, APOB, LDLR and LPL may be new candidate drug targets for the treatment of ED.

Bioavailability and health risk of pollutants around a controlled landfill in Morocco: Synergistic effects of landfilling and intensive agriculture

Toxic contamination of agricultural soils by trace metal(oid)s can pose detrimental effects on human health and agroecological systems. In this view, the current research explored total and available metal(oid)s in surface soils and assessed the associated hazards using pollution indices, PMF modeling, PCA, and Montecarlo probabilistic human risk assessment with 10,000 repetitions. The mean concentrations of Cd, Pb, As, Cr, Ni, Cu, Zn, and Fe were 0.89, 24.86, 1.81, 19.10, 25.44, 7.98, 49.12 and 6183.32 mg kg−1 dry weight, respectively. These findings highlighted that the concentration of pollutants exceeded the values measured in the geochemical background. Soil enrichment by heavy metal (oid)s was confirmed by analyzing available fractions using DTPA ,CaCl2 and enrichment factor (EF). Additionally, pollution indicators (Igeo, PLI, and PERI) displayed significant contamination levels, with a higher ecological risk. Matrix Factorization (PMF) receptor and multivariate statistical analysis reflected that anthropogenic activities, particularly landfilling and agricultural practices were the main causes of the contamination. Furthermore, probabilistic and deterministic human risk assessments showed that carcinogenic risks exceeded the threshold values (10−4) set by the USEPA. Consequently, it is crucial to implement continuous monitoring and supervision of landfill sites to prevent additional pollution. These measures should be integrated into the management plans for waste management.

Prostate Cancer, Race, and Health Disparity: What We Know.

Prostate cancer (PCa) in African American men is one of the most common cancers with a great disparity in outcomes. The higher incidence and tendency to present with more advanced disease have prompted investigators to postulate that this is a problem of innate biology. However, unequal access to health care and poorer quality of care raise questions about the relative importance of genetics versus social/health injustice. Although race is inconsistent with global human genetic diversity, we need to understand the sociocultural reality that race and racism impact biology. Genetic studies reveal enrichment of PCa risk alleles in populations of West African descent and population-level differences in tumor immunology. Structural racism may explain some of the differences previously reported in PCa clinical outcomes; fortunately, there is high-level evidence that when care is comparable, outcomes are comparable.

Evaluation of HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1 polymorphisms associated with prostate cancer in samples of patients from HUPE-UERJ.

Prostate cancer (PCa) is the leading cause of death among men in 48 countries. Genetic alterations play a significant role in PCa carcinogenesis. For the hypothesis of this research, five unique polymorphisms (SNP) were investigated in different genes that showed to be associated in different ways with PCa: rs4430796, rs2735839, rs4792311, rs12329760, and rs28931588, respectively for the genes HNF1B, KLK3, ELAC2, TMPRSS2-ERG, and CTNNB1. Blood samples from 426 subjects were evaluated: 290 controls (161 females and 129 males) and 136 PCa patients. SNP were determined by real-time polymerase chain reaction. TaqMan SNP genotyping assay. In the control samples, the SNPs were defined in association with the self-reported ethnicity, and in 218 control samples with markers with ancestry indicators. The genes were in Hardy-Weinberg equilibrium. One hundred and seventy control samples were matched by ethnicity for comparison with the PCa samples. The G allele at rs28931588 was monomorphic in both patients and controls studied. Significant differences were observed in allelic and genotypic frequencies between the control and Pca samples in rs2735839 (KLK3; p = 0.002 and χ2 = 8.73 and p = 0.01, respectively), by the global frequency and in the dominant model rs2735839_GG (odds ratio [OR] = 0.51, p = 0.02). AA and GA genotypes at rs4792311 (ELAC2) were more frequent in patients with Gleason 7(4 + 3), 8, and 9 (n = 37%-59.7%) compared to patients with Gleason 6 and 7(3 + 4) (n = 26%-40.0%) conferring a protective effect on the GG genotype (OR = 0.45, p = 0.02). The same genotype showed an OR = 2.71 (p = 0.01) for patients with low severity. The HNF1B-KLK3-ELAC2-TMPRSS2-ERG haplotypes: GAAT, AAAT, GAGT, and AAGT were more frequent in patients with Pca with OR ranging from 4.65 to 2.48. Higher frequencies of risk alleles were confirmed in the SNPs, KLK3 rs2735839_A, ELAC2 rs4792311_A, and TMPRSS2 rs12329760_T in patients with Pca. Rs2735839_A was associated with risk of Pca and rs4792311_A with severity and Gleason score of 7(4 + 3) or greater. There is a need for careful observation of rs2735839 and rs4792311 in association with the prostatic biopsy due to the increased risk of Pca.

ANO7 African-ancestral genomic diversity and advanced prostate cancer

BackgroundProstate cancer (PCa) is a significant health burden for African men, with mortality rates more than double global averages. The prostate specific Anoctamin 7 (ANO7) gene linked with poor patient outcomes has recently been identified as the target for an African-specific protein-truncating PCa-risk allele.MethodsHere we determined the role of ANO7 in a study of 889 men from southern Africa, leveraging exomic genotyping array PCa case-control data (n = 780, 17 ANO7 alleles) and deep sequenced whole genome data for germline and tumour ANO7 interrogation (n = 109), while providing clinicopathologically matched European-derived sequence data comparative analyses (n = 57). Associated predicted deleterious variants (PDVs) were further assessed for impact using computational protein structure analysis.ResultsNotably rare in European patients, we found the common African PDV p.Ile740Leu (rs74804606) to be associated with PCa risk in our case-control analysis (Wilcoxon rank-sum test, false discovery rate/FDR = 0.03), while sequencing revealed co-occurrence with the recently reported African-specific deleterious risk variant p.Ser914* (rs60985508). Additional findings included a novel protein-truncating African-specific frameshift variant p.Asp789Leu, African-relevant PDVs associated with altered protein structure at Ca2+ binding sites, early-onset PCa associated with PDVs and germline structural variants in Africans (Linear regression models, −6.42 years, 95% CI = −10.68 to −2.16, P-value = 0.003) and ANO7 as an inter-chromosomal PCa-related gene fusion partner in African derived tumours.ConclusionsHere we provide not only validation for ANO7 as an African-relevant protein-altering PCa-risk locus, but additional evidence for a role of inherited and acquired ANO7 variance in the observed phenotypic heterogeneity and African-ancestral health disparity.

Anogenital distance, a biomarker of fetal androgen exposure and the risk of prostate cancer: A case-control study.

Evaluate the association between AGD and the risk of PCa. Incident case-control study, conducted on 153 patients. All patients underwent prostate biopsy for abnormal digital rectal exam and/or prostate antigen elevation. Two variants of AGD [anus to scrotum base (AGDas) and anus to dorsal insertion of penis (AGDap) were measured. Student's t-test was used to analyze continuous variables and chi-square for discrete variables. Differences in AGD (raw and adjusted) measures between cases and controls were assessed using the ANCOVA test. There is significant association between the diagnose of PCa and both AGD, patients diagnosed with PCa had both AGD measures shortened, in the crude and the full adjusted models. This research suggests that the same gestational environmental exposures, could represent a weak androgen signaling and may also have an increased risk of prostate cancer.

Causal inference between rheumatoid arthritis and prostate cancer.

It is unclear if the association between rheumatoid arthritis (RA) and a higher risk of prostate cancer (Pca) reflects a causal relationship. We conducted a meta-analysis and used the Mendelian randomization method (MR) to evaluate the association between RA and Pca risk. A meta-analysis and subgroup analysis of the incidence of Pca in patients with RA was conducted. To determine whether genetically elevated RA levels were causally linked to Pca, two MR samples were employed. To eliminate gender-related bias, we conducted a stratified analysis of the GWAS data for RA by gender, specifically including 140,254 males. Additional MR analysis was also performed to determine potential confounding factors influencing the association between genetically susceptible RA and Pca. In total, 409,950 participants were enrolled in 20 trials to investigate the Pca risk in patients with RA. The meta-analysis suggested that RA was unrelated to the Pca risk (SIR = 1.072, 95% CI, 0.883-1.261). However, a subgroup analysis showed that low smoking rates might increase the Pca risk in patients with RA by 24%. The MR analysis showed that increased genetic susceptibility to RA was related to a high Pca risk (OR = 36.20, 95%CI = 1.24-1053.12, P = 0.037). The causality estimation of MR-Egger, Weighted mode, Simple mode, and Weighted median method were similar in direction and magnitude. Although our meta-analysis found no correlation between RA and Pca risk, MR analyses supported a causal relationship between genetic susceptibility to RA and increased prostate risk. Early attention to Pca risk in patients with RA may be important for improving prognosis and mortality in such patients. Further research is needed to determine the etiology of RA attributed to Pca and its underlying mechanisms.

Geochemistry pollution status and ecotoxicological risk assessment of heavy metal(oid)s in soil influenced by co-landfilling of MSW and sewage sludge, Morocco

Landfilling activities are one of themajorsources of heavy metal(loid)s contamination. Thus, assessing the spatial distribution ofthese elementsand evaluatingtheirpotentialhazards to public health in the areas surrounding landfills is of utmost importance. In this paper, the synergistic effects of co-landfilling of Municipal Solid Waste (MSW) and Sewage Sludge (SS) were assessed using pollution indicators, PCA, HCA, and Montecarlo probabilistic human risk assessment. To do so, 19 soil, leachate, and sewage sludge samples were collected around the landfill and their content of heavy metal(oid)s was analyzed using Inductively Coupled Plasma (ICP-AES). The average concentrations of As, Cd, Cu, Pb, Zn, Cr, Ni, Co, and Fe were 0.98, 3.14, 36.87, 41.90, 148.43, 21.64, 32.07, 4.02, and 3143.74 mg/kg dry weight, respectively. The concentration of all metal(oid)s was higher than the geochemical background and the highest amount was observed at the first 100 m from the landfill and the sampling sites affected directly by sewage sludge. The values of pollution indexes (geo-accumulation index, enrichment factor, pollution load index, ecological risk index) showedthat soils in the vicinity of the landfill displayed moderate to high contamination level, with a strong potential ecological impact. Furthermore, multivariate statistical analysis demonstrated that anthropogenic sources related to disposal practices of MSW and SS are the main responsible behind the revealed pollution. In addition, the deterministic and probabilistic human risk assessment highlighted that the non-carcinogenic risk for children and adults still within the acceptable limits. However, carcinogenic risk was well above the threshold values (10−4) for children. The elevated pollution level reflected the dangerousness of synergistic dumping of SS and MSW, which renders the avoidance of their co-landfilling mandatory.

Endogenous testosterone density associates with predictors of tumor upgrading and disease progression in the low through favorable intermediate prostate cancer risk categories: analysis of risk factors and clinical implications

BackgroundThe study aimed to test the hypothesis that endogenous testosterone density (ETD), in the low through favorable intermediate PCa risk classes patients undergoing surgery, might be associated with disease progression.Materials and methodsETD, PSAD, and percentage of biopsy positive cores density (BPCD) were calculated in relation to prostate volume (PV). Tumor load density (TLD) was estimated as the tumor load (TL) ratio to prostate weight. ET was considered low if < 230 ng/dL. Tumor upgrading (ISUP > 2), upstaging (pT > 2) and their related features were investigated.Results433 patients were included, 249 (57.5%) from the favorable intermediate-risk class. Upgrading occurred in 168 (38.8%) cases and upstaging in 62 (14.3%). ETD above the median (9.9 ng/(dL x mL)), was discriminated by PSAD (AUC = 0.719; 95% CI: 0.671–0.766; p < 0.0001), BPCD (AUC = 0.721; 95% CI: 0.673–0.768; p < 0.0001), TLD (AUC = 0.674; 95% CI: 0.624–0.724; p < 0.0001) with accuracy improved by the multivariable model (AUC = 0.798; 95% CI: 0.724–0.811; p < 0.0001). In linear multivariable models as ETD increased, so did TLD (rc = 0.019; 95% CI: 0.014; 0.025; p < 0.0001), further increased by low ET (rc = 0.097; 95% CI: 0.017; 0.176; p = 0.017). After adjusting for clinical and pathological features, ETD correlated with TLD above the first quartile. Disease progression occurred in 43 (11.9%) patients, independently predicted by PSAD (hazard ratio, HR = 99.906; 95% CI: 6.519–1531.133; p = 0.001) and tumor upgrading (HR = 3.586; 95% CI: 3.586–6.863; p < 0.0001).ConclusionsETD was associated with unfavorable PCa, and men with tumor upgrading were at increased risk of disease progression. ETD was related to predictors of PCa progression and could provide pivotal biological information about aggressive disease.

Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer

BackgroundProstate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression.MethodsWe analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide expression and matched clinical follow-up data to detect and characterize gene fusions in PCa. With the fusion calling software Arriba, we computationally predicted gene fusions. Following detection, we annotated the gene fusions using published databases for gene fusions in cancer. To relate the occurrence of gene fusions to Gleason Grading Groups and disease prognosis, we performed survival analyses using the Kaplan–Meier estimator, log-rank test, and Cox regression.ResultsOur analyses identified two potential novel gene fusions, MBTTPS2,L0XNC01::SMS and AMACR::AMACR. These fusions were detected in all four studied cohorts, providing compelling evidence for the validity of these fusions and their relevance in PCa. We also found that the number of gene fusions detected in a patient sample was significantly associated with the time to biochemical recurrence in two of the four cohorts (log-rank test, p-value < 0.05 for both cohorts). This was also confirmed after adjusting the prognostic model for Gleason Grading Groups (Cox regression, p-values < 0.05).ConclusionsOur gene fusion characterization workflow revealed two potential novel fusions specific for PCa. We found evidence that the number of gene fusions was associated with the prognosis of PCa. However, as the quantitative correlations were only moderately strong, further validation and assessment of clinical value is required before potential application.

Targeted Biopsy in Men High Risk for Prostate Cancer: 68Ga-PSMA PET/CT Versus mpMRI

Introduction/BackgroundTo evaluate the accuracy of 68Ga-PSMA PET/CT versus mpMRI targeted biopsy (TPBx) in the diagnosis of clinically significant prostate cancer (csPCa) in men high risk for PCa. Materials and MethodsFrom January 2021 to March 2023, 125 men with clinical parameters high risk for PCa were evaluated by mpMRI and 68Ga-PSMA PET/CT; median PSA was 32.5 ng/mL (range: 12-160 ng/mL) and 60/125 (48%) had abnormal digital rectal examination. The mpMRI lesions with PI-RADS scores ≥ 3 and/or 68Ga-PSMA areas characterized by a standardized uptake value (SUVmax) values ≥ 8 were submitted to TPBx (4 cores); in addition, all the patients underwent systematic transperineal prostate biopsy (18 cores) under sedation and antibiotic prophylaxis. ResultsIn 80 of 125 men (64%) a csPCa was found: 10 (12.5%) had a ISUP Grade Group 3 (GG), 45 (56.2%) a ISUP GG4 and 25 (31.2%) ISUP GG5. The median intraprostatic 68Ga-PSMA SUVmax was 42.3 (range:10.5-164) and 72 of 80 (90%) had a PI-RADS score ≥ 3. 68GaPSMA PET/CT showed the presence of metastases in 20 of 80 (25%) men: the median SUVmax in bone (15 cases) and nodes (40 cases) metastases was 55 and 47, respectively. Accuracy of 68Ga PSMA PET/CT (SUVmax cut-off ≥ 8) versus mpMRI PI-RADS score ≥ 3 in the diagnosis of csPCa was 92 versus 86.2%. Conclusion68GaPSMA PET/CT demonstrated a good diagnostic accuracy as a single procedure for the diagnosis and staging of high-risk PCa.

Association of cigarette smoking habits with the risk of prostate cancer: a systematic review and meta-analysis

BackgroundAssociation of cigarette smoking habits with the risk of prostate cancer is still a matter of debate. This systematic review and meta-analysis aimed to assess the association between cigarette smoking and prostate cancer risk.MethodsWe conducted a systematic search on PubMed, Embase, Cochrane Library, and Web of Science without language or time restrictions on June 11, 2022. Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Prospective cohort studies that assessed the association between cigarette smoking habits and the risk of prostate cancer were included. Quality assessment was conducted using the Newcastle–Ottawa Scale. We used random-effects models to obtain pooled estimates and the corresponding 95% confidence intervals.ResultsA total of 7296 publications were screened, of which 44 cohort studies were identified for qualitative analysis; 39 articles comprising 3 296 398 participants and 130 924 cases were selected for further meta-analysis. Current smoking had a significantly reduced risk of prostate cancer (RR, 0.74; 95% CI, 0.68–0.80; P < 0.001), especially in studies completed in the prostate-specific antigen screening era. Compared to former smokers, current smokers had a significant lower risk of PCa (RR, 0.70; 95% CI, 0.65–0.75; P < 0.001). Ever smoking showed no association with prostate cancer risk in overall analyses (RR, 0.96; 95% CI, 0.93–1.00; P = 0.074), but an increased risk of prostate cancer in the pre-prostate-specific antigen screening era (RR, 1.05; 95% CI, 1.00–1.10; P = 0.046) and a lower risk of prostate cancer in the prostate-specific antigen screening era (RR, 0.95; 95% CI, 0.91–0.99; P = 0.011) were observed. Former smoking did not show any association with the risk of prostate cancer.ConclusionsThe findings suggest that the lower risk of prostate cancer in smokers can probably be attributed to their poor adherence to cancer screening and the occurrence of deadly smoking-related diseases, and we should take measures to help smokers to be more compliant with early cancer screening and to quit smoking.Trial registrationThis study was registered on PROSPERO (CRD42022326464).

Abstract B034: A scoping review of carcinogenic potential in prostate cancer from 40+ years of functional vitamin D and K deficiency

Abstract Introduction: Carcinogenesis is a form of accelerated genetic “Darwinian” evolution. Many cells start genetic change. Tobacco tar, an example of extensively researched carcinogen, demonstrates that it takes chronic exposure over 40+ years, accumulating mutations before death with multiple genetic events. Terminal acceleration often includes loss of major histocompatibility (MHC) antigens. Other co-carcinogens, genetic inheritance and chronic inflammation accelerates this process. Experiments, showing that malignant change induced in vitro is much faster than in vivo, suggest that other factors impact on the pace of malignant evolution. Two such factors (DNA repair and immune surveillance) are the best established. As considerable research is targeting DNA repair gene damage, this abstract focuses on latent immunity (less dependent on MHC system than T cell immunity) and its under-performance in carcinogenesis due to Vitamin D and K deficiency. Literature Review terms: Vitamin D(VD), Vitamin K(VK), Cancer, Carcinogenesis, Latent Immunity. Results: Three pieces of evidence that functional long-term VD and VK deficiency could have oncogenic potential were identified. The first was discovery that patients with chronic inflammation had hypermethylation of the VD receptor resulting in failure of the liver to convert stored VD into its active forms. Cancer patients with higher extent of methylation of VD receptor had worse clinical outcomes. Such deficiency is associated with reduced innate immunity due to macrophage dysfunction and this deficiency could increase microbiome dysbiosis. This suggestion is supported by studies linking PCa with 40+ years of persistent infection with the sun-sensitive microaerophilic bacterium Cutibacterium acnes and VD deficiency is linked with increased cancer but limited benefits in VD trials. The second observation is the demonstration that VK2 (Menaquinone) not VK1 (Phylloquinone) deficiency increased risk of PCa. These authors also showed that undercarboxylated osteocalcin, a biomarker of VK2 deficiency, was also linked with risk of PCa. The third observation was evidence from in-vitro breast cancer cell-line studies that Calcitriol plus K2 was synergistic in cytotoxicity assays. Measuring these effects, through the study of the biological age using methylation-based measures PhenoAge and GrimAge because of their relationship between biological aging and cancer, could be useful to monitor in future trials. Conclusions: Combined VD and VK studies have been found safe and beneficial in bone health. This limited review justifies further exploration of this combination in cancer patients. Using serial epigenetic clock scores is justified, given that these clocks are known to improve from diet and exercise interventions. Functional deficiency of VD and VK could be acting as co-carcinogens through enhanced inflammatory process, a precursor in many cancers including those without known carcinogen involvement such as PCa and also involved in accelerating tumour growth after primary treatment. Citation Format: Tim R.D. Oliver, Belinda Nedjai. A scoping review of carcinogenic potential in prostate cancer from 40+ years of functional vitamin D and K deficiency [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B034.