Risk Of Prostate Cancer In Men Research Articles

Polymorphism of Free Radicals Detoxification Genes GSTM1 and GSTT1 is Associated to Prostate Cancer Risk in men: Case Study in Benin

Polymorphism of Free Radicals Detoxification Genes GSTM1 and GSTT1 is Associated to Prostate Cancer Risk in men: Case Study in Benin

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

BackgroundGenetic factors play an important role in prostate cancer (PCa) susceptibility. ObjectiveTo discover common genetic variants contributing to the risk of PCa in men of African ancestry. Design, setting, and participantsWe conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. Outcome measurements and statistical analysisCommon genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. Results and limitationsNine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40–60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10–1.38, p = 4.4 × 10–4). ConclusionsThis study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. Patient summaryIn this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Awareness of genetic risk for prostate cancer (PCa) in men from families with germline mutations in DNA-repair genes.

328 Background: Although one of the most important risk factors for prostate cancer (PCa) is a family history of the disease, there is a poor awareness of genetic risk. The aim of the current study is to investigate the awareness of genetic risk for PCa in men belonging to female families with germline variants in DNA-repair genes (DRGs). Methods: Data were extracted by a prospective observational study designed to select men with germline pathogenic variants (PVs) and offer them a dedicated PCa screening. The selection of probands was performed by genetic counseling and testing of male grade I relatives of female patients with a PVs. Male candidates were identified after reviewing the genealogical trees of all women who had received the diagnosis of breast and/or ovarian cancer and tested positive for a PVs. All the probands, 35-69 yrs old, who resulted positive for PVs were offered to participate to a specific PCa screening based on annually digital rectal examination (DRE), detection of PHI, which is a blood test including total PSA, free PSA, free/total PSA and -2proPSA, and multiparametric MRI. The primary outcome was the “willing to be tested”, defined as a proxy for male awareness of PCa risk. The secondary endpoint was the acceptance rate to be screened. Results: We reviewed the genealogical trees of breast/ovarian cancer female patients from January 2017 to December 2021 and we identified, over 1256 families, 139 positive cases for PVs in DRGs. Among 139 families, we identified 378 “healthy” 35-69 yrs old men, who were offered a genetic counseling, and if they agree a genetic testing. Overall 117/378 (31%) healthy males declared to be interested to be tested. Out of the 51 new tests (66 men already tested out of the study), we found 30 (58.8%) positive men. All the new positive tested men accepted to attend the PCa screening. Living in Northern Italy, having at least one child and higher (degree) level of education were the strongest predictors of willing for testing (p<0.01). Conclusions: Our data reveals a limited will to be tested, but all men tested positive for PVs accepted to participate to the PCa screening. These findings strongly support the urgent need to implement awareness of genetic risk for PCa.

The association between sexual dysfunction and prostate cancer: a systematic review and meta-analysis.

Whether there is a connection between sexual dysfunction (SD) and prostate cancer (PCa) is controversial. We sought to review the interrelationship between SD and PCa and to determine whether there is a definitive risk of men developing PCa after suffering from SD. A complete search of the PubMed, Web of Science, Ovid MEDLINE, Embase, and Cochrane Library databases was performed to search for eligible studies published up to October 2022. The protocol for this meta-analysis is available from PROSPERO (ID: CRD42022342381). The associations between SD and the risk of PCa were assessed by calculating pooled ORs with 95% CIs, and the standard mean difference (SMD) and its 95% CI were used to assess the relationship between SD and prostate-specific antigen (PSA) levels or prostate volume (PV). Random-effects models were used to account for potential heterogeneity, and the Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included studies. Twenty studies involving 215,626 individuals were included in our meta-analysis. Compared with controls, subjects with SD had a 1.62-fold increased risk of PCa (OR = 1.62, 95% CI, 1.77-2.23, P = .003; heterogeneity: I2 = 97.8%, P < .001). Patients with SD had higher PSA levels than controls (SMD =0.07, 95% CI, 0.00 to 0.13, P = .041; heterogeneity: I2 = 55.6%, P = .027). However, there was no association between SD and PV (SMD = 0.03, 95% CI, -0.05 to 0.11, P = .122; heterogeneity: I2 = 48.5%, P = .100). Current evidence confirms a potential link between SD and the risk of PCa and that SD in PCa patients should be of concern to clinicians. The strength of this study is that it is to our knowledge the first meta-analysis of studies on the risk of PCa in men with SD. A limitation is that most of the studies included in this meta-analysis focused on ED. Our systematic review and meta-analysis results suggest that men with SD have a higher risk of PCa and higher PSA levels than men without SD. However, this is merely inferential, and causality cannot be determined based on the current data. Further longitudinal studies should be performed to validate our preliminary findings.

Early prediction of prostate cancer risk in younger men using polygenic risk scores and electronic health records.

Prostate cancer (PCa) screening is not routinely conducted in men aged 55 and younger, although this age group accounts for more than 10% of cases. Polygenic risk scores (PRSs) and patient data applied toward early prediction of PCa may lead to earlier interventions and increased survival. We have developed machine learning (ML) models to predict PCa risk in men 55 and under using PRSs combined with patient data. We conducted a retrospective study on 91,106 male patients aged 35-55 using the UK Biobank database. Five gradient boosting models were developed and validated utilizing routine screening data, PRSs, additional clinical data, or combinations of the three. Combinations of PRSs and patient data outperformed models that utilized PRS or patient data only, and the highest performing models achieved an area under the receiver operating characteristic curve of 0.788. Our models demonstrated a substantially lower false positive rate (35.4%) in comparison to standard screening using prostate-specific antigen (60%-67%). This study provides the first preliminary evidence for the use of PRSs with patient data in a ML algorithm for PCa risk prediction in men aged 55 and under for whom screening is not standard practice.

Association between working hours and cancer risk in Japan: The Japan public health center-based prospective study

In this study, we evaluated the association between working hours and cancer risk in the Japanese population, which has not been evaluated. Using a cohort database from a Japan Public Health Center-based Prospective Study, we evaluated 26 738 participants (16 351 men and 10387 women), who responded to a questionnaire about working hours and followed these participants from 1993-1994 to 2013. Participants were divided into four groups according to working hours (≤6, 7-8, 9-10, ≥11 h/day). The hazard ratio (HR) and 95% confidence interval (CI) of each cancer incidence were calculated using a multivariable-adjusted Cox proportional hazard model. During 488 383 person-years of follow-up, 481 patients with newly diagnosed cancers were identified. There was no clear association between long working hours and overall cancer, lung cancer, and stomach cancer risks. Long working hours tended to increase prostate cancer risk in men and breast cancer risk in women, although the difference was not statistically significant. Increased liver cancer risk with short working hours (HR [95% CI]; 3.15 [1.44-6.88] in the ≤6h/day group vs. 7-8 h/day) was observed. Colorectal cancer also tended to increase risk in short working hours, however, there were not statistically significance. In this population, long working hours were not associated with cancer risk with statistically significance. The association between short working hours and liver cancer risk was observed, probably due to the reverse causation of liver cancer.

Abstract PO-197: Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry

Abstract Introduction: Prostate Cancer (PCa) risk is influenced by both rare germline pathogenic variants (GPVs) in DNA damage repair genes and common variants as measured by polygenic risk scores (PRS) however, the combined effect of GPVs and PRS on PCa risk in men of African ancestry has not been investigated. Methods: We examined the combined effect of rare GPVs and PRS on PCa risk in 1,795 PCa cases and 1,424 controls of African ancestry men from the Multiethnic Cohort, the Los Angeles Study of Aggressive Prostate Cancer, and the Uganda Prostate Cancer Study. GPVs in 19 DNA genes were defined as clinically validated missense variants and variants that alter the protein sequence. The PRS was constructed as a weighted sum of 267 established PCa risk variants. The combined effect of the PRS and GPV status on PCa risk was evaluated using logistic regression models adjusting for age, study, and the first 10 principal components of ancestry to account for population stratification. Results: We identified 91 GPVs carried by 31 controls and 68 cases. Among GPV non-carriers, compared to those with average PRS (33.3-66.7%), odds ratios for PCa ranged from 0.56 (95% CI=0.45-0.70; P=1.2E-7) in low PRS men (0-33.3%) to 3.04 (95% CI=2.54-3.63; P=5.6E-35) in high PRS men (66.7-100%). Among GPV carriers, odds ratios for PCa ranged from 2.09 (95% CI=0.85-5.12; P=0.11) in low PRS men to 5.03 (95% CI=2.37-10.66; P=2.5E-5) in high PRS men, compared to GPV non-carriers with average PRS. Next, we restricted GPVs to ATM, BRCA2, PALB2, and NBN[BD2] (n=51 variants carried by 8 controls and 44 cases), which we previously reported as being the genes most strongly associated with advanced PCa in this population and study sample. Among GPV non-carriers, odds ratios for PCa ranged from 0.56 (95% CI=0.46-0.71; P=2.7E-7) in low PRS men to 5.03 (95% CI=0.85-5.12; P=0.11) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.08 (95% CI=0.58-7.49; P=0.26) in low PRS men to 18.06 (95% CI=4.24-76.84; P=9.0E-5) in high PRS men, compared to average PRS GPV non-carriers. When comparing aggressive cases to controls, considering the top four genes, GPV non-carrier odds ratios for PCa ranged from 0.52 (95% CI=0.40-0.70; P=6.2E-6) in low PRS men to 3.16 (95% CI=2.56-3.91; P=1.6E-26) in high PRS men, while among GPV carriers, odd ratios for PCa ranged from 2.97 (95% CI=073-12.16; P=0.13) in low PRS men to 23.58 (95% CI=5.39-103.20; P=2.7E-5) in high PRS men, compared to average PRS GPV non-carriers. Conclusion: We found that PCa risk in African ancestry men carrying GPVs in DNA damage repair and cancer predisposition genes, particularly ATM, BRCA2, PALB2, and NBN, varied depending on an individual's PRS. This implies that to comprehensively assess genetic risk of PCa, it is important to consider both rare and common variants. These findings could have implications for risk stratification in this high-risk population and emphasize the need for larger genetic studies of PCa in African ancestry men to identify and characterize genetic risk factors in this population. Citation Format: Raymond W. Hughley, Burcu F. Darst, Marco Matejcic, Yesha Patel, Jenna Lilyquist, Steven N. Hart, Eric C. Polley, Lucy Xia, Xin Sheng, Alexander Lubmawa, Sue A. Ingles, Lynne Wilkens, Loïc L. Marchand, Stephen Watya, Fergus J. Couch, David V. Conti, Christopher A. Haiman. Combined effect of a prostate cancer polygenic risk score and germline pathogenic variants in DNA damage repair genes on prostate cancer risk in men of African ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-197.

Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer

Simple SummaryHistorically, the treatment of prostate cancer was a blanket approach for all. Prostate cancer has not benefitted from targeted treatments based on specific tumour characteristics (ie. Particular genetic or molecular patterns) the way other cancers have. This is important as studies have shown that prostate cancer patients with certain errors in their genes, such as BRCA2 or BRCA1, are more likely to have worse disease and poorer outcome. These patients can be treated successfully with a group of drugs called ‘PARP inhibitors’. This paper examines the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined.Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men ≤65 years) making BRCA genes a conceivable genomic biomarker for risk in PCa. These genes have attracted a lot of research attention however their role in the clinical assessment and treatment of PCa remains complex. Multiple studies have been published examining the relationship between prostate cancer and BRCA mutations. Here BRCA mutations are explored specifically as a biomarker for risk in PCa. It is in this context, we examined the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined.

Initial Prostate Health Index (phi) and phi density predicts future risk of clinically significant prostate cancer in men with initial negative prostate biopsy: a 6-year follow-up study.

Men with elevated prostate-specific antigen (PSA) and initial negative prostate biopsy may have risk of prostate cancer (PCa) in the future. The role of Prostate Health Index (phi) in determining future PCa risk has not been studied before. This study aims to investigate the role of initial phi and phi density in predicting future PCa risk in men with initial negative biopsy. Five hundred sixty nine men with PSA 4-10 ng/mL were recruited between 2008 and 2015 for prostate biopsy with prior phi. Electronic clinical record of men with initial negative biopsy was reviewed. Patients and follow-up doctors were blinded to phi. Kaplan-Meier curves were used to analyze the PCa-free survival in different baseline phi and phi density groups. Four hundred sixty-one men with complete follow-up data were included. Median follow-up is 77 months. PCa and HGPCa was diagnosed in 8.2% (38/461) and 4.8% (22/461) of cohort respectively. A higher baseline phi value was associated with PCa (p = 0.003) and HGPCa (p < 0.001). HGPCa was diagnosed in 0.6% (1/163) of phi < 25, 4.6% (9/195) of phi 25-34.9, and 11.7% (12/103) of phi ≥ 35 (p < 0.001). HGPCa was diagnosed in 0% (0/109) and 21.0% (13/62) with phi density of <0.4 and ≥1.2, respectively, (p < 0.001). Kaplan-Meier curves showed phi and phi density predicted PCa and HGPCa diagnoses (log-rank test, all p ≤ 0.002). Initial phi or phi density predicted 6-year risk of PCa in men with initial negative prostate biopsy. Men with higher phi (≥35) or phi density (≥1.2) need closer follow-up and repeated investigation, while men with lower phi (<25) or phi density (<0.4) could have less frequent follow-up.

Digoxin reduces the incidence of prostate cancer but increases the cancer-specific mortality: A systematic review and pooled analysis.

Digoxin, a commonly used drug for congestive heart failure and cardiac arrhythmias, has been reported to exert cytotoxic and apoptosis-inducing effects on prostate cancer (PCa) cells. In this study, we aimed to perform a pooled analysis to summarise all the evidence related to the effects of digoxin on PCa development. Four electronic databases were systematically searched to filter the eligible studies. The hazard ratio (HR) with its 95% confidence interval (CI) was calculated. This study was registered on PROSPERO (ID: CRD42021226885). Ten clinical studies with a total of 108,444 participants (15,835 individuals were digoxin users) were included. The pooled result from 6 included studies demonstrated that digoxin usage was correlated with a significant decrease in PCa risk (adjusted RR=0.892, 95% CI: 0.799-0.997, p=.044) when compared with the nonusers. Synthetic result of 4 eligible studies revealed that digoxin significantly correlated with higher prostate cancer-specific mortality than the controls (adjusted HR=1.142, 95% CI: 1.005-1.297). No statistical heterogeneity was detected during this analysis (all I2 <50%, p>.1). Our study confirmed a preventive effect of digoxin usage for the risk of PCa in men. However, digoxin use was associated with a significantly elevated risk of prostate cancer-specific mortality. This finding needs more well-designed studies to better interpret the causality.

Abstract LB011: Meta-analysis in more than 80,000 men of African ancestry identified nine novel variants associated with prostate cancer

Abstract In search for common genetic variants contributing to the risk of prostate cancer in men of African ancestry, we conducted a meta-analysis of GWAS summary statistics from the African Ancestry Prostate Cancer Consortium (AAPC; 12,643 cases and 16,627 controls) and the VA Million Veteran Program (6,107 cases and 47,412 controls). A total of 29,896,808 common (minor allele frequency (MAF) &amp;gt; 0.01) genotyped and imputed variants (r2 &amp;gt; 0.3) were meta-analyzed in a total of 18,750 prostate cancer cases and 64,039 controls. Of the 269 established risk variants for prostate cancer, 265 were polymorphic and 168 were nominally (P&amp;lt;0.05) associated with prostate cancer risk with directionally consistent effect estimates, of which 44 reached the genome-wide significance (P&amp;lt;5x10-8). Of the 3,018 genome-wide significant variants, eight were considered novel susceptibility loci for prostate cancer in men of African ancestry. Of the eight variants, five were only found in populations of African ancestry (MAF 2% - 34%) but not in European or Asian populations, and two were substantially more common in African ancestry populations (MAF 40%) than in other populations (MAF &amp;lt; 8%). One of the novel variants, rs60985508 (odds ratio (OR) = 1.12 [1.08 - 1.15]; P = 2.93×10-13; MAF = 34%), introduces a stop codon in exon 24 in the prostate-specific gene anoctamin 7 (ANO7), a known prostate cancer susceptibility gene. A polygenic risk score including 273 variants (265 of 269 established risk variants and 8 novel variants from this analysis) conferred an increased prostate cancer risk for men in the 90 - 100th percentile (OR = 3.91 [3.50 - 4.36]) and those in the 99 - 100th percentile (OR = 7.05 [5.51 - 9.02]), compared to men in the 40-60th percentile. These estimates were higher than what was observed with the PRS of 265 variants (90 - 100th percentile: OR = 3.49 [3.13 - 3.90]; 99 - 100th percentile: OR = 6.40 [4.99 - 8.21]). Our finding of 8 novel susceptibility loci for prostate cancer may improve risk prediction for men of African Ancestry and provide further insight into the underlying biology of prostate cancer. Citation Format: Fei Chen, Ravi K. Madduri, Xin Sheng, Alex Rodriguez, Alisha Chou, Todd L. Edwards, Stephen K. Van Den Eeden, Rosalind A. Eeles, John S. Witte, Michael B. Cook, William J. Blot, David V. Conti, John M. Gaziano, Amy C. Justice, Christopher A. Haiman, VA Million Veteran Program and PRACTICAL/ELLIPSE Consortium. Meta-analysis in more than 80,000 men of African ancestry identified nine novel variants associated with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB011.

Dietary intake of polyphenols and total antioxidant capacity and risk of prostate cancer: A case-control study in Iranian men.

Prostate cancer (PCa) is one of the leading causes, globally, of cancer-related mortality. Previous studies have reported an inverse relationship between some food items or dietary patterns and prostate cancer risk. Polyphenols, as antioxidant and anti-inflammatory dietary components, have been associated with a reduced risk of PCa, whilst dietary indices such as total antioxidant capacity are good predictors of PCa risk. The purpose of this study was to conduct a case-control study on the association between polyphenol intake and DTAC (dietary total antioxidant capacity) and PCa risk in men. 205 hospital-based controls and 97 newly diagnosed PCa patients were asked about their dietary intakes using a validated questionnaire. The polyphenol contents (flavonoids, lignans, stilbenes and phenolic acids) of foods and beverages were calculated. TAC was obtained using a comprehensive database consisting of the total antioxidant content of more than 3000 food and beverages. Logistic regression was used to determine the odds ratios (OR), with 95% confidence intervals (CI), of PCa according to categories of polyphenol intake and TAC. When comparing the highest and the lowest tertile of total polyphenol (OR: 0.12; 95% CI: 0.03-0.41), lignans (OR: 0.14; 95% CI: 0.04-0.41), phenolic acids (OR: 0.18; 95% CI: 0.05-0.57) and some flavonoid subgroups intake including flavan-3-ols (OR: 0.24; 95% CI: 0.08-0.67), flavanones (OR: 0.10; 95% CI: 0.03-0.31) and flavones (OR: 0.33; 95% CI: 0.12-0.87), we observed a significant decreasing trend in the risk of PCa (p for trend<0.05). The results suggest that the consumption of some polyphenols can significantly reduce the risk of PCa.

Vitamin D levels and the risk of prostate cancer and prostate cancer mortality

Background Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate. Methods All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25–50 (insufficient), 50–75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied. Results No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45–3.90, p < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33–3.24, p = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency. Conclusion No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

A Quantitative Study of High Intake of Fruits and Vegetables and Prostate Cancer Risk in Men: A Meta-Analysis of Observational Studies

A Quantitative Study of High Intake of Fruits and Vegetables and Prostate Cancer Risk in Men: A Meta-Analysis of Observational Studies

Diagnostic value of PCA3, TMPRSS2:ERG and prostatic specific antigen derivatives in the detection of prostate cancer

Background . Prostate cancer (PCa) is one of the most common malignancy in men. A traditional marker in the laboratory diagnosis ofPCa is the prostatic specific antigen (PSA). However, the low specificity of this marker leads to a large number of unnecessary biopsies. The emergence of various modifications of PSA and tumor-specific genetic markers such as PCA3 and TMPRSS2ERG, have improved the diagnosis of PCa. Objective . Investigation of the diagnostic significance of molecular genetic markers, PCA3 and TMPRSS2:ERG, and their comparison with markers based on PSA isoforms: free/total PSA ratio (%fPSA) and prostate health index (PHI). Materials and methods. The study included 58 men with suspected PCa. All patients were defined PCA3 score and the presence of TMPRSS2:ERG fusion transcript in the urine sediment. Also, PHI and %fPSA were determined in 48 and 51 men, respectively. Results. The area under the ROC-curve regardless of the value of PSA was higher for PCA3 score (0.773, p 95 % PCA3 score had the highest specificity, positive and negative predictive values in men, regardless of the level of PSA: 65.22, 80.95, and 93.75 %, respectively. In men with PSA level of 2—10 ng/ml the area under the ROC-curve for PCA3, %fPSA and PHI was 0.776 (p = 0.001), 0.629 (p = 0.144) and 0.729 (p = 0.009), respectively. At high sensitivity (>95 %) characteristics of the diagnostic test PCA3 in men with a PSA level of 2—10 ng/ml also also exceeded those for PHIand %>fPSA. The negative predictive valuefor PCA3score in this group ofmen was 100 %. The sensitivity ofdetection ofthe TMPRSS2:ERG fusion transcript in urine was 37.14 %, specificity 86.96 %, and the positive predictive value was 81.25 %. Conclusion. The use ofthe PCA3 score in combination with the detection of TMPRSS2:ERG fusion will improve the assessment of PCa risk in men with PSA levels between 2 and 10ng/ml (the “grey zone”).

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

The prostate cancer precision screening program: a preliminary report after recruitment of 2 159 men

Objective: The Chinese Anti-Cancer Association Genitourinary Cancer Committee Prostate Cancer Working Group released Consensus of prostate cancer (PCa) screening in 2017. This program aims to evaluate the methods and significance of prostate cancer precision screening in high risk population. Methods: A total of 2 159 eligible males enrolled from 13 community centers and 3 screening centers received PSA test from April 2017 to August 2018. Prostate-specific antigen (PSA) determination in serum with a cut-off of ≥4.0 ng/ml was the main screening test and indication for biopsy. The interviewer-administered questionnaire covered demographic characteristics and environmental exposure factors. The associations between these factors and prostate cancer risk were determined by multivariable unconditional logistic regression models. Results: Altogether, 271 cases (12.6%) had a confirmed PSA increase ≥ 4.0 μg/L (median 9.1, range 4.0-25.0). Subsequently, 57 subjects (21.0%) out of the 271 PSA-suspicious men underwent prostate biopsy, and 34 (59.6%) were confirmed as prostate cancer. Until now, the overall prostate cancer incidence in the first screening round was1.57%. There were no statistical differences in the distributions of PSA-suspicious and prostate cancer incidence between community centers and screening centers (P=0.578 and 0.735). Age (OR: 2.63; 95%CI: 1.84-3.75, P<0.001) and chronic prostatitis history (OR: 2.02; 95%CI: 1.55-2.63, P<0.001) were significantly associated with PSA level. After adjustment for these factors, older age (OR: 4.04; 95%CI: 1.71-9.59, P=0.002) and statins use (OR: 3.09; 95%CI: 1.25-7.69, P=0.015) were associated with an elevated risk of PCa. Conclusions: It is of substantial significance to screen prostate cancer in high risk population. Both community centers and screening centers methods are effective. Although largely underestimated, the incidence of PCa in the targeted Chinese population is higher than expected. Older men have a high risk of harboring PCa. Our study suggests a decreased risk of PCa in men with statins use. Prostate Cancer Precision Screening is promising to improve prostate cancer survival in China.

Association Between Antidiabetic Medications and Prostate-Specific Antigen Levels and Biopsy Results

Diabetic men appear to have a lower risk of prostate cancer. Whether antidiabetic medications are protective or potentially mask prostate cancer by lowering prostate-specific antigen (PSA) levels is unclear. To examine the associations of antidiabetic medication use with (1) PSA levels, (2) frequency of PSA testing, (3) receipt of biopsy following elevated PSA results, and (4) prostate cancer detection at biopsy. Population-based cohort study using data from the Stockholm PSA and Biopsy Register. Participants were all prostate cancer-free men aged 40 to 79 years residing in Stockholm County, Sweden, between January 1, 2006, and December 31, 2015. Data were analyzed from November 2018 to March 2019. One or more prescription for metformin, sulfonylurea, or insulin, as recorded in Sweden's National Prescribed Drug Register. Levels of PSA following first exposure to antidiabetic medications were assessed using multivariable linear regression. Frequency of PSA testing was assessed via multivariable Poisson regression. Biopsy following elevated PSA (≥3.0 ng/mL) and prostate cancer detection at biopsy were assessed via multivariable logistic regression. The cohort of 564 666 men (median [range] age, 65 [40-79] years) consisted of 4583 men initially exposed to metformin, 1104 exposed to sulfonylurea, and 978 exposed to insulin who were age matched with unexposed men (1:5). Exposed men had lower median (interquartile range) PSA levels before starting antidiabetic medications compared with unexposed men (1.2 [0.7-2.5] vs 1.6 [0.8-3.2] ng/mL). After accounting for baseline differences, PSA levels did not vary from those of unexposed men following exposure to antidiabetic medications. Frequency of PSA testing was higher for those receiving metformin (rate ratio, 1.07; 95% CI, 1.06-1.09) and sulfonylurea (rate ratio, 1.06; 95% CI, 1.03-1.08) but was lower for those receiving insulin (rate ratio, 0.79; 95% CI, 0.77- 0.81). Likelihood of biopsy after elevated PSA was lower among men receiving metformin (odds ratio, 0.87; 95% CI, 0.80-0.96) and insulin (odds ratio, 0.83; 95% CI, 0.74-0.93). There were no differences in prostate cancer detection at biopsy, regardless of PSA levels that triggered the biopsy. This study's findings do not support the hypothesis that the inverse association between diabetes and prostate cancer is mediated through antidiabetic medications lowering PSA levels to mask prostate cancer. They do suggest potential detection bias due to fewer biopsies among men receiving antidiabetic medications, which may explain the lower prostate cancer risk in men with diabetes.

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

A Prospective Study of the Association between Physical Activity and Risk of Prostate Cancer Defined by Clinical Features and TMPRSS2:ERG

BackgroundGrowing evidence shows that clinical and molecular subtypes of prostate cancer (PCa) have specific risk factors. Observational studies suggest that physical activity may lower the risk of aggressive PCa. To our knowledge, the association between physical activity and PCa defined by TMPRSS2:ERG has not been evaluated. ObjectiveTo prospectively examine the association between physical activity and risk of PCa defined by clinical features and TMPRSS2:ERG. Design, setting, and participantsWe studied 49160 men aged 40–75 yr in the Health Professionals Follow-up Study from 1986 to 2012. Data was collected at baseline and every 2 yr with >90% follow-up. Total and vigorous physical activity were measured in metabolic equivalent of task (MET)-h/wk. Outcome measures and statistical analysisAdvanced PCa was defined as stage T3b, T4, N1, or M1 at diagnosis and lethal PCa as distant metastases or death due to disease over follow-up. Presence of TMPRSS2:ERG was estimated by immunohistochemistry of ERG protein expression. Cox proportional hazards models were used to obtain multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of subtype-specific PCa. Results and limitationsDuring 26 yr of follow-up, 6411 developed PCa overall and 888 developed lethal disease. There were no significant associations between total physical activity and risk of PCa in the overall cohort. In multivariable-adjusted models, men in the highest quintile of vigorous activity had a significant 30% lower risk of advanced PCa (HR: 0.70, 95% CI: 0.53–0.92) and 25% lower risk of lethal PCa (HR: 0.75, 95% CI: 0.59–0.94) than men in the lowest quintile of vigorous activity. The association was independent of screening history. Vigorous activity was not associated with total PCa in the overall cohort but was inversely associated among highly screened men (top vs bottom quintile, HR: 0.83, 95% CI: 0.70–0.97). Of all cases, 945 were assayed for ERG (48% ERG-positive). Men with higher vigorous activity had a lower risk of ERG-positive PCa (top vs bottom quintile, HR: 0.71, 95% CI: 0.52–0.97). There was no significant association with the risk of ERG-negative disease (p heterogeneity=0.09). ConclusionsOur study confirms that vigorous physical activity is associated with lower risk of advanced and lethal PCa and provides novel evidence for a lower risk of TMPRSS2:ERG-positive disease. Patient summaryThe identification of modifiable lifestyle factors for prevention of clinically important prostate cancer (PCa) is needed. In this report, we compared risk of PCa in men with different levels of physical activity. Men with higher vigorous activity had a lower risk of developing advanced and lethal PCa and PCa with the common TMPRSS2:ERG gene fusion.