Increased Risk Of Prostate Cancer Research Articles

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

Simple SummaryCurrent cancer testing gene panels tend to be comprehensive. One of the genes commonly included in the testing panels is BARD1. To establish whether BARD1 mutations predispose to prostate cancer, we sequenced BARD1 in 390 hereditary prostate cancer cases, genotyped 5715 men with unselected prostate cancer and 10,252 controls for three recurrent rare BARD1 variants in Poland. We did not see an elevated prostate risk cancer given p.Q564X truncating mutation, p.R658C missense mutation and p.R659= synonymous variant. Neither variant influenced prostate cancer characteristics or survival. Our study is the first to evaluate the association between BARD1 mutations and prostate cancer susceptibility. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested, because BARD1 is a breast cancer susceptibility gene.The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p-values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene.

Factors Contributing to Bladder Filling Variability in Patients Receiving Radiotherapy for Prostate Cancer

Prostate cancer patients receiving radiotherapy (RT) are treated with full bladders to minimize bladder dose and displace bowel from the treatment field. While limitations in controlling bladder filling reproducibility during RT have been shown to affect bladder and bowel dosimetry, the factors affecting bladder volume variability have not been elucidated. We herein evaluate the impact of prostate cancer risk group, bladder volume (BV) at the beginning of treatment, and pre-treatment International Prostate Symptom Score (IPSS) on metrics quantifying BV changes during RT.We retrospectively reviewed 78 prostate cancer patients treated from 2016-19 with definitive RT 8,100 cGy in 45 fractions (n = 32), definitive stereotactic body RT 3625 cGy in 5 fractions over 2.5 weeks (n = 24), and adjuvant or salvage RT 7020 cGy in 39 fractions (n = 22). Thirty-six patients with high or unfavorable intermediate risk disease received androgen deprivation therapy (ADT) prior to RT, while 29 patients with high risk disease received pelvic nodal RT in addition to prostate or prostate bed RT. Each patient completed a pre-treatment IPSS survey and received daily cone-beam CT (CBCT) scans for positioning during treatment. The BV at beginning of treatment was defined as the patient's first attempt to fully fill his bladder without assistance. BVs were contoured on the CT simulation scan and CBCT images from the first and last days of radiotherapy. Age, risk group, IPSS and initial BV were compared with change in BV (ΔBV), change in BV relative to initial BV (%Δ) and absolute change in BV (|ΔBV|) between first and last day of RT.Median age and IPSS were 69 (range 50-84) years and 8 (0-30), respectively. Mean and standard deviation initial BV, ΔBV, %ΔBV and |ΔBV| were 314 ± 152 cc, -59 ± 123 cc, -8 ± 40%, 106 ± 85 cc, respectively. On multivariable analysis, initial BV was negatively correlated with ΔBV and %ΔBV independent of age, prostate cancer risk group, ADT, pelvic nodal RT, and duration of treatment (P < 0.05). Initial BV and prostate cancer risk group were positively, while IPSS was negatively, correlated with |ΔBV| (P < 0.05).Prostate cancer patients with large initial BV experienced larger total and relative declines in BV during RT. High initial BV, increasing prostate cancer risk group, and low IPSS correlated with greater absolute changes in BV (|ΔBV|) over the course of treatment. Hence, maximizing bladder volume during simulation appears to negatively impact reproducibility, which must be taken into consideration when optimizing bladder volume reproducibility using a non-invasive approach during prostate radiotherapy. We have already implemented these findings into our simulation and treatment protocols and look forward to reporting our clinical outcomes in the near future.

MP36-09 URINARY FUNCTION AND PROSTATE SAFETY OF LONG-TERM TESTOSTERONE THERAPY (TTh) IN MEN WITH FUNCTIONAL HYPOGONADISM IN A UROLOGICAL REGISTRY STUDY

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy II (MP36)1 Sep 2021MP36-09 URINARY FUNCTION AND PROSTATE SAFETY OF LONG-TERM TESTOSTERONE THERAPY (TTh) IN MEN WITH FUNCTIONAL HYPOGONADISM IN A UROLOGICAL REGISTRY STUDY Ahmad Haider, Karim Sultan Haider, Gheorghe Doror, and Abdulmaged Traish Ahmad HaiderAhmad Haider More articles by this author , Karim Sultan HaiderKarim Sultan Haider More articles by this author , Gheorghe DororGheorghe Doror More articles by this author , and Abdulmaged TraishAbdulmaged Traish More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002045.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: According to current guidelines, there is no evidence for an increased risk for prostate diseases with testosterone therapy (TTh). Concerns are still common in general practice as well as urology offices. To provide more data from clinical experience, we analyzed a registry database of men with functional hypogonadism. METHODS: 779 men with functional hypogonadism were analysed. 386 men received testosterone undecanoate injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 393 opted against TTh and served as controls (CTRL). 11-year results were analyzed. Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between groups. RESULTS: Baseline age: 58.4±6.4 (T-group), 63.1±4.8 years (CTRL) (p<0.0001). At baseline, alpha-blockers were used by 44.3% (T-group) and 50.4% (CTRL) (p=0.1534), 5α-reductase inhibitors by 2.6% and 8.4% (p<0.0005), and PDE5-Inhibitors by 25.9% and 22.1% (p=0.2181). T-group: IPSS declined by 5.1±0.1 in year 11. CTRL: IPSS increased by 4.1±0.1. Estimated adjusted difference between groups at 11 years: -9.2 (p<0.0001 for all). Prostate volume increased by 3.1±0.2 mL (T-group) and by 3.9±0.2 mL (CTRL) (p<0.0001 for both), difference between groups: -0.8 mL (p<0.01). PSA increased by 0.06±0.1 ng/mL (T-group) (p=0.5508) and by 1.1±0.1 ng/mL (CTRL) (p<0.0001), difference between groups: -1.0 (p<0.0001). Prostate cancer (PCa) incidence: 12 patients (3.1%) in the T-group were diagnosed with PCa, 50 (12.7%) in CTRL (p<0.0001). All PCas in the T-group were diagnosed within 18 months after receiving the first injection of TU. In CTRL, PCa was diagnosed at any time during the observation period. Only in CTRL, biochemical recurrence occurred in 18 (36%) patients. These patients received LHRHa. 18 (36%) patients died of whom 11 were on LHRHa. CONCLUSIONS: Long-term TTh in men with functional hypogonadism improved urinary function which worsened in untreated controls. TTh was not associated with an increased PCa risk. The fact that PCa in the T-group was always detected within the first 18 months of TTh suggests that TTh unveiled PCa that had previously been undetectable. Incidence of PCa was four times higher in untreated patients with functional hypogonadism, suggesting a protective effect of maintaining stable testosterone levels. Source of Funding: Data entry and statistical analysis was compensated by Bayer AG. © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e639-e639 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmad Haider More articles by this author Karim Sultan Haider More articles by this author Gheorghe Doror More articles by this author Abdulmaged Traish More articles by this author Expand All Advertisement Loading ...

Association of 5-Alpha Reductase Inhibitor Use with Prostate Specific Antigen Level at the Time of Urology Referral in a Retrospective Cohort at a Large, Integrated Health Care System.

5-Alpha reductase inhibitor (5-ARI) use leads to a 50% decline in serum prostate specific antigen (PSA) without a concomitant decrease in prostate cancer (PCa) risk. We hypothesize that failure to account for the effect of 5-ARI use on serum PSA leads to increased PCa risk at urology referral among 5-ARI users. This is a retrospective cohort study for the years 2018-2019. Atrium Health is a large, vertically integrated health system with over 900 care locations in North Carolina and South Carolina. Men ≥40 years old during 2018-2019 who had a PSA test performed were included. We determined differences in corrected serum PSA level at the time of referral to urology. 5-ARI users and nonusers were compared using the chi-square test, Student's t-test and gamma regression. From 2018-2019, there were 91,368 men who underwent PSA testing, including 2,939 5-ARI users. At referral, 5-ARI users had similar uncorrected median PSA (5.8 vs 5.6 ng/ml, p=0.05). After correcting for the effect of 5-ARIs on PSA, 5-ARI users had a median PSA of 11.6 ng/ml at urology referral, compared to 5.6 ng/ml in nonusers. Men taking 5-ARIs have higher corrected serum PSA at time of referral to urology. As the unadjusted PSA at referral to urology for PCa risk was similar between 5-ARI users and nonusers, this indicates that the effect of 5-ARI use on serum PSA levels is not routinely accounted for when assessing PCa risk.

A case-control study investigating the association of TP53 rs1042522 and CDH1 rs16260 polymorphisms with prostate cancer risk

ObjectivesProstate cancer is the most frequent non-cutaneous malignancy in men. Numerous genetic factors play a crucial role in the progression of prostate cancer. This study was undertaken to reveal the correlation of TP53 rs1042522 and CDH1 rs16260 polymorphisms with the risk of prostate cancer in the Bangladeshi population. Materials and methodsWe recruited 210 prostate cancer patients and 210 healthy controls for the investigation. Genotyping was conducted using the PCR-RFLP technique. ResultsIn case of TP53 gene rs1042522, the association analysis revealed that all genetic models were linked with significantly increased risk for prostate cancer development (CG vs. CC: OR = 1.99, p = 0.001; GG vs. CC: OR = 4.82, p < 0.00; CG vs. CC + GG: OR = 1.52, p = 0.041; CG + GG vs. CC: OR = 2.44, p < 0.00; GG vs. CC + CG: OR = 3.64, p = 0.00; G vs. C: OR = 2.32, p < 0.00). Again, the second variant rs16260 in CDH1 gene also showed significantly enhanced association in all genetic models for the development of prostate cancer (CA vs. CC: OR = 2.20, p < 0.00; AA vs. CC: OR = 2.77, p = 0.012; CA vs. CC + AA: OR = 1.98, p = 0.001; CA + AA vs. CC: OR = 2.29, p = 0.00; A vs. C: OR = 1.99, p < 0.00) except the AA vs. CC + CA model. ConclusionsOur study indicates a significant association of TP53 rs1042522 and CDH1 rs16260 polymorphisms with increased prostate cancer risk in the Bangladeshi population. However, replication studies are required in different populations to validate our findings.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

In1-Ghrelin Splicing Variant as a Key Element in the Pathophysiological Association Between Obesity and Prostate Cancer.

Recent studies emphasize the importance of considering the metabolic status to develop personalized medicine approaches. This is especially relevant in prostate cancer (PCa), wherein the diagnostic capability of prostate-specific antigen (PSA) dramatically drops when considering patients with PSA levels ranging from 3 to 10 ng/mL, the so-called grey zone. Hence, additional noninvasive diagnostic and/or prognostic PCa biomarkers are urgently needed, especially in the metabolic-status context. To assess the potential relation of urine In1-ghrelin (a ghrelin-splicing variant) levels with metabolic-related/pathological conditions (eg, obesity, diabetes, body mass index, insulin and glucose levels) and to define its potential clinical value in PCa (diagnostic/prognostic capacity) and relationship with PCa risk in patients with PSA in the grey zone. Urine In1-ghrelin levels were measured by radioimmunoassay in a clinically, metabolically, pathologically well-characterized cohort of patients without (n = 397) and with (n = 213) PCa with PSA in the grey zone. Key obesity-related factors associated with PCa risk (BMI, diabetes, glucose and insulin levels) were strongly correlated to In1-ghrelin levels. Importantly, In1-ghrelin levels were higher in PCa patients compared to control patients with suspect of PCa but negative biopsy). Moreover, high In1-ghrelin levels were associated with increased PCa risk and linked to PCa aggressiveness (eg, tumor stage, lymphovascular invasion). In1-ghrelin levels added significant diagnostic value to a clinical model consisting of age, suspicious digital rectal exam, previous biopsy, and PSA levels. Furthermore, a multivariate model consisting of clinical and metabolic variables, including In1-ghrelin levels, showed high specificity and sensitivity to diagnose PCa (area under the receiver operating characteristic curve = 0.740). Urine In1-ghrelin levels are associated with obesity-related factors and PCa risk and aggressiveness and could represent a novel and valuable noninvasive PCa biomarker, as well as a potential link in the pathophysiological relationship between obesity and PCa.

Relevance of Interleukins 6 and 8 Single Nucleotide Polymorphisms in Prostate Cancer: A Multicenter Study.

The diverse roles of cytokines as IL-6 and IL-8 have been studied in terms of their SNPs in many diseases but their role in prostate cancer (PCa) is still uncertain. Aim. To determine the relevance of IL-6 rs1800795 SNP and/or IL-8 rs2227306 SNP with prostate cancer's risk. Subjects and Methods. 40 PCa patients, 40 benign prostate hyperplasia (BPH) patients, and 40-age-matched-control group were enrolled in the study. Genotyping of IL-6 rs1800795 (G/C) SNP and IL-8 rs2227306 (C/T) SNP was determined using real-time PCR. Results. High frequency of IL-6 rs1800795GG and IL-8 rs2227306CC genotypes was noticed among PCa patients with associated OR 10.091 and 8.143, respectively. Comparisons based on allele frequencies revealed that IL-6G and IL-8C alleles are more frequent among PCa patients than other groups. Presence of IL-6 rs1800795G and IL-8 rs2227306C alleles in the same patient increase PCa risk by 16.7 times. Statistical correlations between PSA ratio and both of IL-6 and IL-8 SNP did not show any significant relation among PCa patients. Conclusion. IL-6 rs1800795G and IL-8 rs2227306C alleles could be considered risk factors for PCa development, particularly if presented together. However, no relation was found between both cytokines SNP and severity of prostate cancer.

The Association between Dietary Diversity Score and Risk of Prostate Cancer: (A Case-Control Study)

There are few studies that evaluated the relationship between dietary diversity score (DDS) and risk of cancer. The purpose of this study was to examine the association of DDS with the risk of prostate cancer (PC) among Iranian men. This case-control study was performed among 60 cases with prostate cancer and 60 hospital-based controls. Anthropometric measurements were done and demographic information was recorded using standard protocols. A validated 160-item semi-quantitative food frequency questionnaire (FFQ) was used to assess usual dietary intakes. Also, Binary logistic regression was performed to estimate the risk of PC in relation to DDS. After controlling for several confounders (age, body mass index, physical activity, energy intake, job, education, and antihypertensive drugs usage) higher adherence to DDS (OR = 0.33; 95% CI (0.11-0.97)), fruits group (OR = 0.19; 95% CI (0.06-0.63)), and vegetables group (OR = 0.17; 95% CI (0.05 − 0.58)) were significantly associated with lower risk of PC. In contrast, greater adherence to the meat group (OR = 3.88; 95% CI (1.32-11.42)) was significantly associated with increased PC risk. Our results showed that adherence to a diet with higher DDS, especially higher amounts of fruits and vegetables and a lower amount of meat could decrease the risk of PC.

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.

The CYP19A1 (TTTA)n Repeat Polymorphism May Affect the Prostate Cancer Risk: Evidence from a Meta-Analysis.

Abnormal aromatase (CYP19A1) expression may participate in prostate cancer (PCa) carcinogenesis. However, the results of studies on the CYP19A1 gene polymorphisms and PCa are conflicting. This meta-analysis aimed to systematically evaluate the associations between the CYP19A1 Arg264Cys polymorphism and the (TTTA)n repeat polymorphism and PCa. Electronic databases (PubMed, EmBase, ScienceDirect, and Cochrane Library) were comprehensively searched to identify eligible studies. The strength of the association between the Arg264Cys polymorphism and PCa was assessed by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) in allelic, dominant, recessive, homozygous, and heterozygous genetic models. To analyze the impact of the (TTTA)n repeat polymorphism, we sequentially took the N-repeat allele (where N equals 7,8,10,11,12, and 13) as the minor allele and the sum of all the other alleles as the major allele. The ORs and 95% CIs were calculated in the allelic model; this analysis was performed individually for each repeat number. Pooled estimates of nine studies addressing the Arg264Cys polymorphism indicated that this polymorphism was not associated with PCa risk in the overall population or in the Caucasian or Asian subgroups. The 8-repeat allele in the (TTTA)n repeat polymorphism increased PCa risk in the overall population (OR = 1.34, 95% CI = 1.14–1.58, p = .001) and in the subgroup with population-based (PB) controls (OR = 1.41, 95% CI = 1.13–1.74, p = .002) as well as in the subgroup using capillary electrophoresis to identify this polymorphism (OR = 1.34, 95% CI = 1.09–1.65, p = .006).The meta-analysis indicated that the CYP19A1 (TTTA)n repeat polymorphism, but not the Arg264Cys polymorphism, may affect PCa risk.

Research advances in the relationship of dietary factors and prostate cancer risk

Prostate cancer is the second most common malignancy in men worldwide. An increasing trend for prostate cancer incidence was observed in China. Enormous studies have been conducted to investigate the association between dietary factors and prostate cancer, however conflicted results were obtained. Red meat, processed meat, and dairy products consumption were reported to be associated with the increased prostate cancer risk, while tomatoes, soybeans and green tea might reduce the risk of prostate cancer occurance. However, no consensus could be reached without strong evidence. Furthermore, further studies are needed to investigate the association between vitamin and mineral supplements and prostate cancer risk. Some studies reported that men with higher dietary inflammatory index scores increased prostate cancer risk. There may be a long susceptible period when dietary factors affect prostate cancer risk, which poses challenges for collecting exposure and the follow-up. Measure bias and detection bias are the main reasons which impair the authenticity of studies on the relationship of dietary factors and prostate cancer risk. Researchers should apply various methods to measure participants' dietary consumption levels and ascertain essential outcomes, such as prostate cancer death. This article reviews updated epidemiological evidences on the association of dietary factors and prostate cancer, aims to benefit future nutritional epidemiology studies focus on the prostate cancer prevention.

Inflammatory bowel disease and risk of urinary cancers: a systematic review and pooled analysis of population-based studies.

BackgroundThe aim of this study is to elucidate the risk of urologic cancers in patients with Crohn’s disease (CD) and ulcerative colitis (UC).MethodsElectronic databases including PubMed, the Cochrane Library, Embase and Web of Science, and manual retrieval were conducted from inception to June 2020. Two reviewers independently searched the above databases and selected the studies using prespecified standardized criteria. The Newcastle-Ottawa Scale was used to assess the risk of bias in the included studies, and this meta-analysis was completed by STATA version 14.2.ResultsA total of 12 cohort studies and 4 case-control studies were included in this meta-analysis. Overall, patients with inflammatory bowel disease (IBD) were at significantly increased risk of renal cancer (RCa) [standardized incidence ratio (SIR): 1.53; 95% confidence interval (CI): 1.25–1.80; I2=42.4%], but not at increased risk of prostate cancer (PCa), bladder cancer (BCa) and male genital cancer. In the subgroup analysis, CD patients had a significantly higher RCa risk (SIR: 1.95; 95% CI: 1.45–2.44; I2=39.9%). Besides, CD patients seemed to be at borderline significantly increased risks of PCa (SIR: 1.07; 95% CI: 0.93–1.20; I2=15.1%) and BCa (SIR:1.19; 95% CI: 0.94–1.44; I2=0%), and UC patients seemed to be at borderline significantly increased risks of RCa (SIR:1.31; 95% CI: 0.94–1.67; I2=48.0%) and PCa (SIR: 1.13; 95% CI: 0.93–1.33; I2=73.5%). Notably, we observed that IBD patients in Eastern countries have significantly increased PCa risk (SIR: 2.66; 95% CI: 1.52–3.81; I2=13.6%), especially for UC patients (SIR: 3.01; 95% CI: 1.75–4.27; I2=0.0%).ConclusionsOur findings indicate that IBD patients with special reference to CD patients increase the risk of RCa. Besides, IBD patients in Asian countries have significantly increased risk of PCa, especially for UC patients. Further studies are warranted to elucidate the potential mechanism of RCa associated with IBD and the differences of the risk of urinary cancers between Eastern and Western countries.

Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease.

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

A Latent Disease Model to Reduce Detection Bias in Cancer Risk Prediction Studies.

In studies of cancer risk, detection bias arises when risk factors are associated with screening patterns, affecting the likelihood and timing of diagnosis. To eliminate detection bias in a screened cohort, we propose modeling the latent onset of cancer and estimating the association between risk factors and onset rather than diagnosis. We apply this framework to estimate the increase in prostate cancer risk associated with black race and family history using data from the SELECT prostate cancer prevention trial, in which men were screened and biopsied according to community practices. A positive family history was associated with a hazard ratio (HR) of prostate cancer onset of 1.8, lower than the corresponding HR of prostate cancer diagnosis (HR = 2.2). This result comports with a finding that men in SELECT with a family history were more likely to be biopsied following a positive PSA test than men with no family history. For black race, the HRs for onset and diagnosis were similar, consistent with similar patterns of screening and biopsy by race. If individual screening and diagnosis histories are available, latent disease modeling can be used to decouple risk of disease from risk of disease diagnosis and reduce detection bias.

Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer

BackgroundHyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. ObjectiveTo determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. Design, setting, and participantsWe prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986–2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. Outcome measurements and statistical analysisTotal, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns—empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern—and prostate cancer risk estimated using Cox proportional hazard regression. Results and limitationsDuring 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01–1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00–1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06–1.35) for advanced, 1.22 (1.04–1.42) for fatal, and 1.20 (1.04–1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00–1.35). ConclusionsHyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. Patient summaryAvoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.

Does inflammatory bowel disease increase the risk of lower urinary tract tumors: a meta-analysis.

BackgroundInflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is characterized by chronic inflammation that could be a risk factor for extraintestinal cancer. The aim of this study is to evaluate whether inflammatory bowel disease is related to the risk of lower urinary tract tumors.MethodsA systematical research was performed on various medical databases including PubMed, the Cochrane Library, Embase and Web of Science from inception to April 2020. Data were independently extracted by two reviewers. The Newcastle-Ottawa Scale and the Oxford Centre for Evidence-Based Medicine criteria were used to assess the quality of included articles. The analysis was completed by STATA version 14.2.ResultsSix hundred and twelve of records were initially identified and 16 studies were included in the final analysis. In general, inflammatory bowel disease patients were not at increased risk of prostate cancer, bladder cancer and male genital cancer. In the subgroup analysis, Crohn’s disease patients seemed to have borderline increased risk of prostate cancer [standardized incidence ratio: 1.05; 95% confidence interval (CI): 0.90–1.21; I2=15.1%] and bladder cancer (standardized incidence ratio: 1.19; 95% CI: 0.94–1.44; I2=0.0%), and ulcerative colitis patients seemed to have borderline increased risk of prostate cancer (standardized incidence ratio: 1.13; 95% CI: 0.93–1.33; I2=73.5%).ConclusionsInflammatory bowel disease did not significantly increase the risk of prostate cancer, bladder cancer and male genital cancer. Crohn’s disease patients seemed to have a higher risk of prostate cancer and bladder cancer, and ulcerative colitis patients seemed to have a higher risk of prostate cancer. ulcerative colitis patients in East Asian countries have significantly increased prostate cancer risk.

Social Jetlag and Prostate Cancer Incidence in Alberta's Tomorrow Project: A Prospective Cohort Study.

Simple SummaryDue to social obligations (e.g., school, work), people shift their sleep and activity time regardless of their sleep-wake preference. To compensate for the lack of sleep accumulated over the workdays, people tend to oversleep on a work-free day. This difference in sleep timing between workdays and free days resembles traveling across different time zones, which causes jetlag (a mild form of circadian disruption). Thus, it is named social jetlag. Social jetlag has been linked with obesity, metabolic disorders, and cardiovascular risk in previous research. This study assessed social jetlag in 7455 cancer-free men in Alberta’s Tomorrow Project and followed them for on average 9.6 years, 250 men were diagnosed with prostate cancer. The study found that the more social jetlag men experienced, the greater their prostate cancer risk was. This finding warrants future research to better understand the complex behavioral and biological pathways between social jetlag and prostate cancer risk.We investigated the association of social jetlag (misalignment between the internal clock and socially required timing of activities) and prostate cancer incidence in a prospective cohort in Alberta, Canada. Data were collected from 7455 cancer-free men aged 35–69 years enrolled in Alberta’s Tomorrow Project (ATP) from 2001–2007. In the 2008 survey, participants reported usual bed- and wake-times on weekdays and weekend days. Social jetlag was defined as the absolute difference in waking time between weekday and weekend days, and was categorized into three groups: 0–<1 h (from 0 to anything smaller than 1), 1–<2 h (from 1 to anything smaller than 2), and 2+ h. ATP facilitated data linkage with the Alberta Cancer Registry in June 2018 to determine incident prostate cancer cases (n = 250). Hazard ratios (HR) were estimated using Cox proportional hazards regressions, adjusting for a range of covariates. Median follow-up was 9.57 years, yielding 68,499 person-years. Baseline presence of social jetlag of 1–<2 h (HR = 1.52, 95% CI: 1.10 to 2.01), and 2+ hours (HR = 1.69, 95% CI: 1.15 to 2.46) were associated with increased prostate cancer risk vs. those reporting no social jetlag (p for trend = 0.004). These associations remained after adjusting for sleep duration (p for trend = 0.006). With respect to chronotype, the association between social jetlag and prostate cancer risk remained significant in men with early chronotypes (p for trend = 0.003) but attenuated to null in men with intermediate (p for trend = 0.150) or late chronotype (p for trend = 0.381). Our findings suggest that greater than one hour of habitual social jetlag is associated with an increased risk of prostate cancer. Longitudinal studies with repeated measures of social jetlag and large samples with sufficient advanced prostate cancer cases are needed to confirm these findings.

Fatherhood status in relation to prostate cancer risks in two large U.S.-based prospective cohort studies.

BackgroundDespite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa.MethodsWe examined participants of two cohorts, the NIH‐AARP Diet and Health (NIH‐AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence.ResultsFatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH‐AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH‐AARP (p trend < 0.01), despite none of the individual categorical point estimates reaching this threshold.ConclusionThis study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship.

Dietary Factors and Supplements Influencing Prostate-Specific Antigen (PSA) Concentrations in Men with Prostate Cancer and Increased Cancer Risk: An Evidence Analysis Review Based on Randomized Controlled Trials

The quest for dietary patterns and supplements efficient in down-regulating prostate-specific antigen (PSA) concentrations among men with prostate cancer (PCa) or increased PCa risk has been long. Several antioxidants, including lycopene, selenium, curcumin, coenzyme Q10, phytoestrogens (including isoflavones and flavonoids), green tea catechins, cernitin, vitamins (C, E, D) and multivitamins, medicinal mushrooms (Ganoderma lucidum), fruit extracts (saw palmetto, cranberries, pomegranate), walnuts and fatty acids, as well as combined supplementations of all, have been examined in randomized controlled trials (RCTs) in humans, on the primary, secondary, and tertiary PCa prevention level. Despite the plethora of trials and the variety of examined interventions, the evidence supporting the efficacy of most dietary factors appears inadequate to recommend their use.