Increased Risk Of Prostate Cancer Research Articles

Abstract 3430: Mosaic loss of the Y chromosome is associated with prostate cancer risk

Abstract Mosaic loss of the Y chromosome (mLOY), a type of clonal hematopoiesis, is the most frequent chromosomal alteration observed in leukocytes of aging men. mLOY is a putative biomarker of genomic instability with evidence of associations with risk of some solid tumors, but more studies are needed to refine associations and identify potential mechanisms for cancer risk. Prostate cancer (PCa), the most common non-cutaneous cancer in males, is also associated with aging. To further investigate potential relationships between mLOY and PCa, we examined DNA derived from leukocytes of male participants in two large biobanks: the UK Biobank (UKBB; N = 210,103) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N = 26,795). Of the 236,898 male participants without previous cancer diagnosis, 14,253 (6.0%) were diagnosed with incident PCa after DNA collection. High-density genotyping array data collected during the studies were used to create virtual karyotypes for detecting mLOY in whole blood samples utilizing a phase-based detection method in MoChA software. Analyses were restricted to men without cancer at genotyping and multivariable regression models were adjusted for age, smoking status, and genetic similarity. Men with detectable mLOY were older (mean = 62 vs 56 years) and more likely to be smokers (14.8% vs 9.7%) than men without mLOY. A total of 3,848 (27.0%) men with PCa and 42,835 (19.2%) men free of PCa had detectable mLOY. mLOY clonal fraction ranged from 0.01% to 72.1% of total leukocytes. 18.7% of PCa cases and 13.6% of men free of PCa had high clonal fraction mLOY, defined as greater than 10% of leukocytes with mLOY. Fixed effect meta-analysis of multivariable models from UKBB and PLCO produced evidence for a positive association between mLOY in leukocytes and incident PCa; (Odds Ratio (OR) = 1.062, 95% Confidence Interval (CI) [1.020, 1.107], P-Value (p) = 0.004). The effect estimate was the same in men with low clonal fraction of mLOY (OR = 1.062, 95% CI [1.012, 1.113], p = 0.014) and men with high clonal fraction of mLOY (OR = 1.065, 95% CI [0.998, 1.137], p = 0.057). Age at PCa diagnosis was not associated with mLOY or the clonal fraction of mLOY. A sub-analysis of separate participants from PLCO with mLOY detected in buccal cells (n = 18,011) also showed a small positive effect between mLOY and PCa risk, but the relationship did not reach statistical significance (OR = 1.036, 95% CI [0.877, 1.224], p = 0.673)). Our investigation of the relationship between mLOY and PCa in two large prospective studies provides additional evidence for an association between mLOY detected in the blood and increased PCa risk, meriting additional studies of potential biologic mechanisms underlying the relationship. Citation Format: Rebecca L. Kelly, Weiyin Zhou, Kara M. Barnao, Corey D. Young, Aubrey K. Hubbard, Sairah M. Khan, Wen-Yi Huang, Stephen J. Chanock, Mitchell J. Machiela. Mosaic loss of the Y chromosome is associated with prostate cancer risk [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 3430.

Drug-target Mendelian randomization revealed a significant association of genetically proxied metformin effects with increased prostate cancer risk.

The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied metformin effects with prostate cancer risk using a drug-target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls). Cis-expression quantitative trait loci (cis-eQTL) variants in the gene targets of metformin were identified in the GTEx project and eQTLGen consortium. We also obtained male-specific genome-wide association study data for type 2 diabetes, body mass index (BMI), total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin for mediation analysis. Inverse-variance weighted (IVW) regression, weighted median, MR-Egger regression, and MR-PRESSO were performed in the main MR analysis. Multivariable MR was used to identify potential mediators and genetic colocalization analysis was performed to assess any shared genetic basis between two traits of interest. We found that genetically proxied metformin effects (1-SD HbA1creduction, equivalent to 6.75 mmol/mol) were associated with higher risk of prostate cancer (odds ratioIVW [ORIVW]: 1.55, 95% confidence interval,CI: 1.23-1.96, p = 3.0 × 10-3). Two metformin targets, mitochondrial complex I (ORIVW: 1.48, 95%CI: 1.07-2.03, p = 0.016) and gamma-secretase complex (ORIVW: 2.58, 95%CI:1.47-4.55, p = 0.001), showed robust associations with prostate cancer risk, and their effects were partly mediated through BMI (16.4%) and total testosterone levels (34.3%), respectively. These results were further supported by colocalization analysis that expressions of NDUFA13 and BMI, APH1A, and total testosterone may be influenced by shared genetic factors, respectively. In summary, our study indicated that genetically proxied metformin effects may be associated with an increased risk of prostate cancer. Repurposing metformin for prostate cancer prevention in general populations is not supported by our findings.

Prognostic Factors in Prostate Cancer Associated with Ulcerative Colitis.

Ulcerative colitis (UC) has been associated with increased prostate cancer (PCa) risk. However, the mechanisms underlying UC and increased PCa risk remain unclear, and research on this topic is scarce in Japan. We have investigated whether UC is associated with PCa risk in the Japanese population and the risk factors related to PCa among older UC patients. This retrospective single-center cohort study was conducted between January 2010 and April 2022. A total of 68 cases were analyzed, and 9 cases of PCa were observed (13.2%). PCa occurred more frequently in the adult-onset group (8/40, 20.0%) than in the older-onset group with UC (1/28; 3.57%). No significant differences were observed between immunosuppressive therapies and PCa in patients, excluding those with pancolitis-type UC. PCa occurred more frequently in the pancolitis type, and the biologics group had no PCa cases, but the difference was not statistically significant (p = 0.07). This study suggests that pancolitis type and UC onset in middle-aged patients may be risk factors and found that biologics potentially suppress PCa development.

Association of ulcerative colitis and acute gastroenteritis with prostate specific antigen: results from National Health and Nutrition Examination Survey from (2009 to 2010) and Mendelian randomization analyses.

An increasing number of studies have demonstrated that gastrointestinal inflammation may increase prostate cancer risk and raise the prostate-specific antigen (PSA) level. However, the association between ulcerative colitis (UC) and acute gastroenteritis (AGE) with PSA remains unclear and complicated. Herein, we evaluated the relationship between UC and AGE with PSA concentration using the National Health and Nutrition Examination Survey (NHANES) database and Mendelian randomization (MR) analyses. A total of 1,234 participants fit into the study after conducting the screening based on the NHANES survey conducted from 2009 to 2010. UC and AGE were the independent variables, and PSA was the dependent variable. Weighted multiple linear regressions were utilized to estimate the association of UC and AGE with PSA concentration. To detect the causal relationship between UC and AGE with PSA, a two-sample Mendelian randomized analysis was conducted. After controlling for all covariates, PSA (log2 transform) concentrations in the UC group were increased by 0.64 (0.07, 1.21). AGE was not independently associated with PSA levels after adjusting potential confounders. In patients with coronary artery disease, AGE promotes elevated PSA (log2 transform) concentrations (β = 1.20, 95% CI: 0.21-2.20, p < 0.001). Moreover, an IVW MR analysis indicated that genetically predicted UC was associated with increased PSA, and that AGE was not associated with PSA. This study indicated that a positive causal association exists between UC and the PSA level. However, there is no evidence to support the relationship between AGE and the PSA level.

Abstract C087: Association of serum lipid profile with prostate cancer risk and aggressiveness in Nigerian men

Abstract OBJECTIVE Though prostate cancer (PCa) is the most common cancer and cause of cancer death among Nigerian men, its relationship with serum lipid profiles, a biochemical measurement of dietary fat, has not been explored among Nigerian men. The study aimed to determine the association of serum lipid profile with prostate cancer risk and aggressiveness. METHODS The study was a case-control conducted at University College Hospital, Ibadan, Nigeria. The cases were newly diagnosed prostate cancer patients ages 50-75 years, while the controls were age-matched healthy men with confirmed normal PSA. Participants with uncontrolled comorbidities, poor performance status (ECOG ≥3), and weight loss in the past month were not eligible. The patient characteristics (age, marital status, employment status, highest level of education, high-fat diet, lack of exercise, tobacco smoking, alcohol intake, family history of prostate cancer, comorbidities, and tumor characteristics [PSA at presentation, histology, Gleason score, and stage at presentation] in the cases alone) were collected using an interviewer-administered questionnaire. A serum lipid profile test (including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) was done in all participants. Analysis of the variables was on SPSS version 23.0, with a t-test to compare the serum lipid profile between the case and control groups, a chi-square to compare the sociodemographic and patient characteristics between both groups and an ANOVA test to determine the association between serum lipid profile and Gleason's score (disease grade) or stage of prostate cancer. RESULTS Enrolled in each group were seventy-four participants. The mean age ± standard deviation was 65.0 ± 5.9 years for cases and 63.0 ± 6.5 years for controls. Participants with a high-fat diet (p = 0.006), physical inactivity (p = 0.046), alcohol consumption (p = 0.005), and family history (p = 0.002) were significantly higher in the case group than the controls. A high proportion of the cases had high-grade disease (GS ≥ 8) [39.2%] and stage 4 disease (35.2%). The mean levels of TC (p&amp;lt;0.001) and HDL-C (p&amp;lt;0.001) were significantly higher in the cases. The mean TG increased while HDL-C decreased as the disease stage advanced but with no statistical significance. While the mean TC (p = 0.001) increased significantly with worsening prostate cancer grade, the mean HDL-C was highest in low-grade disease (p &amp;lt;0.001). CONCLUSION Elevated total cholesterol and high-density lipoprotein cholesterol were associated with increased prostate cancer risk. While elevated total cholesterol was associated with high-grade prostate cancer, a high level of high-density lipoprotein cholesterol was associated with the low-grade disease. Hence, regular serum lipid profile tests may be encouraged among Nigerian men for early detection and treatment of any cholesterol derangement to avoid its predisposition to prostate cancer. Citation Format: Kehinde Oluwatosin Adeyinka, Adeniyi Adenipekun, Atara Ntekim, Augustine Oghenewveyin Takure, Rotimi Solomon. Association of serum lipid profile with prostate cancer risk and aggressiveness in Nigerian men [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C087.

Interleukins-6 −174G/C (rs1800795) and −572C/G (rs1800796) polymorphisms and prostate cancer risk

Prostate cancer (PCa) is an aggressive cancer influenced by a complex interplay of genetic and environmental factors. Amongst these risk factors, the impact of Interleukin6 (IL6) gene polymorphisms in PCa risk has received a lot of attention. IL-6 is a cytokine that has been implicated in the pathogenesis of several malignancies, including PCa. Two IL-6 gene polymorphisms, − 174 G/C (rs1800795) and − 572 C/G (rs1800796), have received intellectual attention due to their potential role as modulators of prostate cancer risk. The main objective of this research was to comprehensively explore the potential associations between IL-6 rs1800795 and rs1800796 polymorphisms, and their impact on the occurrence of PCa. A case-control study was carried out with a well-defined cohort comprising 110 PCa cases and 110 controls (total n = 220). The genotyping of rs1800795 and rs1800796 was carefully performed using the highly sensitive and accurate Polymerase Chain Reaction-High Resolution Melting Curve (PCR-HRM) technique. The assessment of genetic associations was evaluated using various R packages, such as Haplo-Stats, SNP stat, pheatmap, and LD heatmap. The present study applied odds ratio (OR) analysis to reveal significant evidence of strong associations between the genotypes of rs1800795 and rs1800796 and the susceptibility to PCa. The findings of this study underscore the noteworthy impact of genetic variations in the IL-6 gene on the development of prostate cancer. Specifically, the C/G and G/G genotypes of rs1800795 demonstrated increased PCa risk, with odds ratios (OR) of 1.650 (95% CI = 1.068–2.549, p = 0.032) and 2.475 (95% CI = 1.215–5.043, p < 0.001), respectively. Similarly, the G/C genotype of rs1800796 exhibited an OR of 2.374 (95% CI = 1.363–4.130, p = 0.012) for elevated prostate cancer risk, while the C/C genotype had an OR of 1.81 (95% CI = 1.02–3.22, p = 0.7). Furthermore, our haplotype analysis have revealed an association between haplotype 4 (C-G) and increased risk of PCa (OR = 1.69, 95% CI = 1.05–2.73, p = 0.032). In conclusion, this case-control analysis presents compelling evidence for a significant association between IL-6 variants (rs1800795 and rs1800796) and increased susceptibility to prostate cancer.

Association of PSA variability with prostate cancer development using large-scale medical information data: a retrospective cohort study

BackgroundProstate cancer is one of the most common cancers among men worldwide and the fourth most common cause of death. The number of prostate cancer cases and deaths is increasing every year because of population aging. This study aimed to clarify the risk of developing prostate cancer due to fluctuations in Prostate Specific Antigen (PSA) levels in patients without a history of prostate cancer using large medical information data.ResultsThis retrospective cohort included 1707 male patients aged 60 years or older who had a PSA level measurement date (2-PSA) within 3 months or more and 2 years from the first PSA level measurement date (1-PSA) in the database between 2008 and 2019. We subtracted 1-PSA from 2-PSA and designated patients with a higher 2-PSA than 1-PSA to the “up” group (n = 967) and patients with a lower 2-PSA than 1-PSA to the “down” group (n = 740). By using Cox proportional hazards model, a significant increase in prostate cancer risk was observed in the up group compared with the down group (adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.21–2.72; adjusted for patient background factors). Subgroup analysis showed that patients with PSA levels < 4 ng/mL had a significantly increased risk of developing prostate cancer if the next PSA level increases by approximately 20% (adjusted HR = 2.94, 95% CI = 1.14–7.58), and patients with PSA levels of 4 ng/mL or higher if the next PSA level is decreased by approximately 20% had a significantly reduced risk of developing prostate cancer (adjusted HR = 0.36, 95% CI = 0.18–0.74), compared to that with no change.ConclusionsThis is the first study to clarify the association between PSA variability and risk of developing prostate cancer in patients without a history of prostate cancer. These results suggest that the suppression of elevated PSA levels may lead to the prevention of prostate cancer and that it would be better to perform a biopsy because the risk of developing prostate cancer may increase in the future if the PSA value increases above a certain level.

Chronic Glucocorticoid Use and Risk for Advanced Prostate Cancer at Presentation: A SEER-Medicare Cohort Study

BackgroundExamine the relationship between exposure to systemic glucocorticoids (steroids) and advanced prostate cancer (PCa) at presentation. Prior work suggested that steroid use may be associated with increased PCa risk. Materials and MethodsWe queried the linked SEER-Medicare database (2004-2015) to identify PSA screened patients diagnosed with PCa. Criteria for screening included a PSA lab test or DRE exam in both the 12 month and 13 to 36 month periods prior to diagnosis of PCa. Steroid exposure was determined using Medicare Part D and groups were divided based on duration of use in the 3 years prior to diagnosis: controls with no exposure, <30 days, 30 days – 1 year, 1 to 2 years, and >2+ years. Advanced PCa was defined as systemic metastases or regional lymph node metastasis at presentation. Risk estimates for advanced PCa at presentation for steroid exposure groups vs. controls were assessed with univariable and multivariable logistic regression models. ResultsWe identified 22,920 PSA screened patients diagnosed with PCa of which 29% used glucocorticoids in the exposure period. The mean (SD) duration for glucocorticoid use (in days) among all steroid users was 76.7 days (192.1). On univariable and multivariable analyses, > 2 years of steroid exposure was associated with significantly increased risk for advanced PCa (OR 2.06, 95% CI 1.35-3.14 and OR 1.74, 95% CI 1.12-2.69, respectively). ConclusionIn this population-based PSA-screened cohort, prolonged steroid use was associated with increased risk of advanced PCa at diagnosis. With the widespread use of glucocorticoids, it is important to consider the role steroids may play in PCa pathogenesis.

Joint associations between established genetic susceptibility loci, pesticide exposures, and risk of prostate cancer

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06–1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09–2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.

Intake of the Total, Classes, and Subclasses of (Poly)Phenols and Risk of Prostate Cancer: A Prospective Analysis of the EPIC Study.

Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HRlog2 = 0.99, 95% CI 0.94-1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.

Obesity and prostate cancer screening, incidence, and mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Though obesity, measured by body mass index (BMI), is an established risk factor for several cancer sites, there is conflicting evidence on whether obesity increases prostate cancer risk or mortality and, if it does, whether it increases risk directly or indirectly by affecting prostate cancer screening efficacy. We examined associations between BMI and prostate cancer screening outcomes, incidence, and mortality in men randomly assigned to the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (n = 36 756) between 1993 and 2001. Participants received annual screening with the prostate-specific antigen test and digital rectal exam. Associations between baseline BMI and screening outcomes were assessed via multinomial logistic regression, and associations with prostate cancer incidence and mortality were assessed via Cox proportional hazards regression. Individuals with higher BMI were less likely to screen positive via the prostate-specific antigen test and/or digital rectal exam and more likely to have an inadequate screen (all Ptrend < .01). Higher BMI was inversely associated with prostate cancer incidence (per 5 kg/m2 BMI increase: hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.91 to 0.97), including incidence of early stage (HR = 0.94, 95% CI = 0.90 to 0.97) and advanced-stage (HR = 0.91, 95% CI = 0.82 to 1.02) disease, but positively associated with prostate cancer mortality (HR = 1.21, 95% CI = 1.06 to 1.37). The association with mortality was not modified by screening outcome (Pinteraction = .13). Within this screened population, individuals with higher BMI had lower risk of prostate cancer diagnosis but higher risk of prostate cancer mortality. As higher BMI was not positively associated with advanced-stage prostate cancer risk, the increased mortality is unlikely to be due to delayed prostate cancer detection.

Abstract A025: Elevated periprostatic fat is associated with high grade prostate cancer in radiotherapy-treated patients

Abstract Introduction Obesity is associated with poor prostate cancer-specific outcomes. Body mass index, a commonly used surrogate of obesity, does not adequately describe fat distribution, which can instead be assessed using medical imaging. Abdominal visceral obesity, a better indicator of metabolic health, has been associated with increased prostate cancer risk. Similarly, periprostatic adipose tissue (PPAT), a type of visceral fat in close proximity to the prostate has a postulated role in prostate cancer aggressiveness. We hypothesised that elevated quantities of visceral fat, both abdominal and periprostatic would be associated with increased disease aggressiveness. To gain insight into potential contributing mechanisms, we examined gene expression pathways differentially expressed in association with adiposity measures. Methods Abdominal adipose tissue, both subcutaneous and visceral (n=244), and PPAT (n=309) were quantified from the radiation planning computed tomography (CT) scans from prostate cancer patients treated with radiotherapy and ADT in the Northern Ireland Cancer Centre between 2005-2009. Abdominal fat was measured at L4/L5 and PPAT at the midpoint of pubic symphysis using a threshold of -190 to -30 Hounsfield Units to identify fat. Associations of adipose tissue quantity, categorised using tertiles of fat quantity, with Gleason score (≥4+3 versus ≤3+4) were assessed using univariable and multivariable logistic regression analysis. Associations between adipose tissue quantity and risk of biochemical recurrence and metastasis were examined using Cox regression. In a subset of patients with tumour biopsy transcriptomic data (n=183), an exploratory Gene Set Enrichment Analysis (GSEA) was performed to identify enriched gene pathways in the tumours of those with high versus low fat measures, defined using the median fat quantity. Results High PPAT was significantly associated with increased risk of high grade prostate cancer (Tertile 3 vs. Tertile 1; age adjusted OR 2.05; 95%CI 1.17-3.62; p=0.01). There was a trend for increased risk of high grade disease in those with high abdominal subcutaneous (T3 vs. T1; age adjusted OR 1.73; 95%CI 0.92-3.30) and visceral (T3 vs. T1; age adjusted OR 1.21; 95%CI 0.66-2.25) fat measures but this was not significant. In GSEA, those with high PPAT showed enrichment of the KEGG adipocytokine signalling pathway (nominal p-value=0.004) whilst those with high subcutaneous fat had enrichment of pathways involved in lipid and cholesterol metabolism. No adipose tissue measure was significantly associated with prostate cancer-specific outcomes following a median follow up of 10.1 years. Conclusions Elevated quantities of PPAT are associated with increased risk of high grade prostate cancer and enriched tumour adipocytokine signalling, suggesting a possible paracrine role of PPAT in prostate cancer aggressiveness. This is the first study to explore potential mechanisms of PPAT using tumour gene expression data. If confirmed, this may in part explain the link between obesity and aggressive prostate cancer. Citation Format: Sarah J. Winter, Suneil Jain, Gillian Prue, Conor K. McGarry, Alan R. Hounsell, Michelle Leech, Emma H. Allott. Elevated periprostatic fat is associated with high grade prostate cancer in radiotherapy-treated patients [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 A025.

Diagnosis of high-grade prostate cancer in patients with unexpectedly low prostate specific antigen levels: a rare case series

Link of Video Abstract: https://youtu.be/PfhZ7H4kszQ Background: Prostate cancer is regarded as one of the most common leading causes of male cancer-related death worldwide. Clinicians agree that prostate specific antigen (PSA) is the best prostate cancer predictor. High PSA levels increase prostate cancer risk in most men. However, other research suggests that prostate cancer with low PSA levels is aggressive. In this uncommon case series, we present three high-grade prostate cancer patients with low PSA. Case Description: Between 2018 and 2019, three patients were referred for further therapeutic management after initial evaluation and treatment from secondary hospitals. All patients underwent complete diagnostic procedures including Laboratory examination, Pathological examination, and Radiologic imaging. PSA levels were 0.67 ng/mL, 4.0 ng/ml, and 4.93 ng/mL in the first, second, and third patients, respectively. The first two of three patients had a Gleason score (GS) of 9 (5+4), and one patient presented with GS of 8 (5+3). Distant metastatic disease was not found in our series. All of the patients underwent hormonal therapy, and none of them underwent radical prostatectomy. Follow-ups were completed in all patients, with the survival of 3 months, 4 months, and 12 months respectively. Conclusion: High-grade prostate cancer in patients with low PSA levels emphasizes the need for rigorous history taking and physical examination and quick investigation of new biomarkers and criteria for prostate cancer detection. These patients' prognosis and optimal therapy are unknown. These patients have a worse prognosis than those with high PSA values, according to multiple studies.

Systemic lupus erythematosus and prostate cancer risk: a pool of cohort studies and Mendelian randomization analysis

BackgroundCurrent observational studies suggest that there may be a causal relationship between systemic lupus erythematosus (SLE) and prostate cancer (PC). However, there is contradictory evidence. This study aimed to investigate and clarify the association between SLE and PC.MethodsWe searched PubMed, Embase, Web of Science, and Scopus until May 2022. A meta-analysis was conducted on the standard incidence rate (SIR) and 95% CI. Subgroup analysis was performed based on the follow-up duration, study quality, and appropriate SLE diagnosis. Mendelian randomization (MR) of the two samples was used to determine whether genetically elevated SLE was causal for PC. Summary MR data were obtained from published GWASs, which included 1,959,032 individuals. The results were subjected to sensitivity analysis to verify their reliability.ResultsIn a meta-analysis of 79,316 participants from 14 trials, we discovered that patients with SLE had decreased PC risk (SIR, 0.78; 95% CI, 0.70–0.87) significantly. The MR results showed that a one-SD increase in genetic susceptibility to SLE significantly reduced PC risk (OR, 0.9829; 95% CI, 0.9715–0.9943; P = 0.003). Additional MR analyses suggested that the use of immunosuppressants (ISs) (OR, 1.1073; 95% CI, 1.0538–1.1634; P < 0.001), but not glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs), which were associated with increased PC risk. The results of the sensitivity analyses were stable, and there was no evidence of directional pleiotropy.ConclusionsOur results suggest that patients with SLE have a lower risk of developing PC. Additional MR analyses indicated that genetic susceptibility to the use of ISs, but not GCs or NSAIDs, was associated with increased PC risk. This finding enriches our understanding of the potential risk factors for PC in patients with SLE. Further study is required to reach more definitive conclusions regarding these mechanisms.

The association between serum lipid profile and the prostate cancer risk and aggressiveness.

This study aims to evaluate the association of serum lipid profile on prostate cancer (PC) risk and aggressiveness. Men who underwent prostate biopsy between January 2005 and December 2015 were retrospectively analyzed. The association between lipid profile and the risk, stage, and Gleason grade group (GG) of the PC were investigated. Sensitivity analysis was conducted using univariate and multivariate quantile analysis for lipide profile on the risk and stage of PC. Of the 1740 study populations, 720 men (41.4%) were diagnosed as PC. From multivariate logistic regression analysis, age, prostate specific antigen, triglyceride (odds ratio (OR):1.05, confidence interval (CI):1.03-1.07, p-value<0.001) significantly increased PC risk, while total cholesterol (OR:0.96, CI:0.92-0.99, p-value=0.011) significantly decreased the PC risk. The increase of serum triglyceride increased the risk of both of locally advanced (OR:1.03, CI:1.00-1.07, p-value=0.025) and metastatic PC (OR:1.14, CI:1.04-1.25, p-value=0.004). The increase of serum triglyceride increased the risk of GG2-3 (OR:1.03, CI:1.00-1.06, p-value=0.027) and GG4-5 (OR:1.04, CI:1.01-1.08, p-value=0.027). Univariate quartile analysis founded serum triglyceride increasing risk of locally advanced disease than organ confined disease. (OR: 1.00, 1.25, 2.04, 4.57 for 1st, 2nd, 3rd and 4th quartile, p-value<0.001). Adjusted multivariate quartile analysis confirmed statistically significant increasing PC risk of triglyceride (OR: 1.00, 1.25, 2.04, 4.57 for 1st, 2nd, 3rd and 4th quartile, p-value<0.001). This study findings suggested increased in triglyceride level increased the risk PC. Increased in triglyceride level also associated with aggressive presentation of PC, with higher stage and GG.

Blood pressure, calcium channel blockers, and the risk of prostate cancer: a Mendelian randomization study.

Observational studies have found some evidence of an association between elevated blood pressure and prostate cancer risk; however, the results are inconclusive. We tested whether systolic blood pressure (SBP) influences prostate cancer risk and evaluated the effect of calcium channel blockers (CCB) on the disease using Mendelian randomization (MR) approach. We used 278 genetic variants associated with SBP and 16 genetic variants in CCB genes as instrumental variables. Effect estimates were obtained from the UK Biobank sample of 142,995 males and from PRACTICAL consortium (79,148 cases and 61,106 controls). For each 10mm Hg increase in SBP the estimated effect was OR 0.96 (0.90-1.01) for overall prostate cancer; and OR 0.92 (0.85-0.99) for aggressive prostate cancer. The MR-estimated effect of a 10mm Hg- SBP lowering through CCB genetic variants was OR 1.22 (1.06-1.42) for all prostate cancers and OR 1.49 (1.18-1.89) for aggressive prostate cancer. The results of our study did not support a causal relationship between SBP and prostate cancer; however, we found weak evidence of a protective effect of high SBP on aggressive prostate cancer and we found that blocking calcium channel receptors may increase prostate cancer risk.

A cohort study evaluating the clinical, environmental and genetic profiles of men with early-onset, aggressive prostate cancer.

266 Background: The frequency of young men with aggressive prostate cancer (PC) at diagnosis is increasing. Clinical, environmental, and genetic drivers of this change have not been well characterized. Methods: This multi-institutional study evaluated two cohorts; Cohort 1 completed enrollment and is reported here. Eligible patients (pts) had early-onset (age ≤ 60 years) PC with metastasis (N+ or M+) at diagnosis, or within 5 years of curative intent local therapy. Data were collected to define clinical, environmental, and genetic profiles, including ctDNA and whole genome and transcriptome sequencing using Tempus xE. Standard descriptive statistics were used. Results: 46 pts were enrolled. Median age at diagnosis was 55 (range 41-60 years); 85% were White, 15% were Black; 4% served in the military and 4% reported biochemical exposure. 85% reported a family history of cancer, 46% had family history of PC. Median PSA at diagnosis was 19 (range 1-534 ng/mL), 56% had a Gleason score of 9-10, and 56% had de novo metastatic PC. 46% had prior local therapy. Genetic data is available for 40 pts. The most frequent clinically significant mutations (≥10% for somatic, ≥2.5% for germline) are summarized. 23 unique germline and over 1,000 unique somatic mutations were identified. Germline mutations associated with hereditary PC were found in 15%, all were associated with DNA damage repair (DDR). Somatic mutations in DDR genes were found in 10%. Co-mutations in TP53 and BRAF were seen in 30%. Interestingly, there were also incidental germline mutations identified that are associated with cardiac ( MYBPC, MYH7) and vascular ( MYH11, ACTA2) conditions, among others. Conclusions: In this cohort study we identified an unexpectedly high frequency of family histories that were positive for cancer (85%), and specifically PC (46%). However, rates of germline mutations associated with hereditary PC were similar to previous studies (15%), suggesting the possibility that other novel hereditary mutations driving increased PC risk may be present. Increased rates of somatic mutations in BRAF (35%) were also seen. The high frequency of BRAF mutations, particularly those that co-occur with TP53 mutations, may be driving more aggressive disease. We also found enrichment of mutations associated with non-cancer hereditary syndromes, including hypertrophic cardiomyopathy. These are not usually included in cancer-focused genetic studies, suggesting broader testing that includes potentially actionable incidental findings should be considered. More work is needed to define characteristics of this high-risk population and optimize management. [Table: see text]

Prostate cancer risk, screening and management in patients with germline BRCA1/2 mutations.

Mutations in the BRCA1 and BRCA2 tumour suppressor genesare associated with prostate cancer risk; however, optimal screening protocols for individuals with these mutations have been a subject of debate. Several prospective studies of prostate cancer incidence and screening among BRCA1/2 mutation carriers have indicated at least a twofold to fourfold increase in prostate cancer risk among carriers of BRCA2 mutations compared with the general population. Moreover, BRCA2 mutations are associated with more aggressive, high-grade disease characteristics at diagnosis, more aggressive clinical behaviour and greater prostate cancer-specific mortality. The risk for BRCA1 mutations seems to be attenuated compared with BRCA2. Prostate-specific antigen (PSA) measurement or prostate magnetic resonance imaging (MRI) alone is an imperfect indicator of clinically significant prostate cancer; therefore, BRCA1/2 mutation carriers might benefit from refined risk stratification strategies. However, the long-term impact of prostate cancer screening is unknown, and the optimal management of BRCA1/2 carriers with prostate cancer has not been defined. Whether timely localized therapy can improve overall survival in the screened population is uncertain. Long-term results of prospective studies are awaited to confirm the optimal screening strategies and benefits of prostate cancer screening among BRCA1/2 mutation carriers, and whether these approaches ultimately have a positive impact on survival and quality of life in these patients.

Genetic association in CYP3A4 and CYP3A5 genes elevate the risk of prostate cancer

Background CYP3A4 and CYP3A5 are biologically potential genes responsible for prostate cancer. Aim We aimed to analyse the expression and association of CYP3A4 and CYP3A5 genes in prostate cancer. Subjects and methods Web-based bioinformatics tools were used to assess the association of CYP3A4 and CYP3A5 genes with prostate cancer risks. A case-control study of 210 prostate cancer cases and 207 controls was also approved to determine the allelic variants of the CYP3A4 gene- rs2740574 (CYP3A4*1B) and the variant of CYP3A5 gene-rs776746 (CYP3A5*3) using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). The risk of prostate cancer was estimated as odds ratio (OR) and 95% confidence interval (CI) using unrestricted logistic regression models. Results Our in silico data confirmed that both CYP3A4 and CYP3A5 genes are significantly associated with higher prostate cancer risks. In the case of CYP3A4*1B polymorphism, the heterozygote (*1 A/*1B), mutant (*1B/*1B), and combined heterozygote plus mutant (*1A/*1B+*1B/*1B) genotypes showed 3.52-fold, 3.90-fold, and 3.67-fold increased risk of prostate cancer, respectively. In the case of CYP3A5*3 polymorphism, the heterozygote (*1/*3), mutant (*3/*3), and combined (*1/*3+*3/*3) genotypes were found to be significantly associated with 5.11-, 5.49-, and 5.28-fold greater risk of prostate cancer, respectively. Conclusion Our results indicate that CYP3A4*1B and CYP3A5*3 are significantly associated with increased prostate cancer risk.

Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression.

Genetic variants in super-enhancers (SEs) are increasingly implicated as a disease risk-driving mechanism. Previous studies have reported an associations between benzo[a]pyrene (BaP) exposure and some malignant tumor risk. Currently, it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk, nor the associated intrinsic molecular mechanisms. In the current study, by using logistic regression analysis, we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk (odds ratio = 1.26, P = 7.61 × 10 -5). We also have found that the rs6001092T>G, in a high linkage disequilibrium with rs5750581T>C ( r 2 = 0.98), is located in a regulatory aryl hydrocarbon receptor (AhR) motif and may interact with the FAM227A promoter in further bioinformatics analysis. We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene. Biologically, the rs6001092-G allele strengthened the transcription factor binding affinity to AhR, thereby upregulating FAM227A, especially upon exposure to BaP, which induced the malignant phenotypes of prostate cancer. The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk, which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.