Non-aggressive Prostate Cancer Research Articles

Neighborhood Disadvantage and Prostate Tumor Aggressiveness among African American and European American Men.

Studies have identified associations between neighborhood disadvantage (ND), which is more likely to affect African American (AA) individuals, and aggressive prostate cancer. Thus, ND may contribute to prostate cancer disparities. However, it is unknown what ND components drive aggressive disease and whether associations vary by race. We evaluated associations between aggressive prostate cancer and four ND metrics-Area Deprivation Index (ADI), validated Bayesian Neighborhood Deprivation Index (NDI), racial isolation (RI) index, and historical redlining, and whether these factors interacted with race, among men with prostate cancer treated at the University of Maryland Greenebaum Comprehensive Cancer Center (2004-2021). We included 1,458 men (698 European American and 760 AA). AA men were more likely to experience ND. In adjusted models, the ADI, RI, and redlining were significantly associated with aggressive versus nonaggressive prostate cancer overall [ADI, OR for one SD increase = 1.14, 95% confidence interval (CI), 1.00-1.30; RI, OR = 1.27, CI, 1.07-1.51; redlining, OR = 1.77; CI, 1.23-2.56] and among AA men. The NDI was associated with aggressive prostate cancer among AA men (OR = 1.32, 95% credible interval: 1.13-1.57); percent in poverty received the largest importance weight. The ADI (P heterogeneity = 0.002) and NDI (exceedance probability heterogeneity = 98.1%) significantly interacted with race, such that associations were significantly stronger for AA men. We identified novel significant positive associations for racial segregation and historical redlining with aggressive prostate cancer and significant interactions between ND indices and race. Findings inform specific ND components that are associated with aggressive prostate cancer and suggest the ND effect is stronger for AA men, which has implications for interventions to reduce disparities.

Correlation of testosterone and ESR2 in prostate cancer

Introduction: Prostate cancer (PCa), as the second most frequent cancer in males, has a significant challenge in determining differential diagnosis and prognosis of aggressive or non-aggressive prostate cancer. For functioning correctly, the prostate needs sex steroid hormones, which are also factors in the initiation and progression of carcinogenesis. Risk and Gleason score upgrading can be predicted by preoperative plasma testosterone levels in men with prostate cancer undergoing radical prostatectomy. Not only testosterone but estrogen also has roles in prostate cancer carcinogenesis. Estrogen Receptor 2 (ESR2) gene has been found to encode ER-β, which has an anti-proliferative effect on prostate tissue. This study aims to look up any correlation between testosterone and ESR2 in prostate cancer. Methods: This is an analytic cross-sectional study. We conducted a quantitative real-time polymerase chain reaction (qPCR) examination involving 15 benign prostate hyperplasia (BPH), 10 non-metastasized PCa, and 21 PCa patients for determining ESR2 expression from formalin-fixed paraffin-embedded (FFPE) prostate cancer tissue with known testosterone level in our institution. Data were analyzed using statistical tests with a significance of p <0.05. Results: The mean testosterone level and ESR2 expression are 785 ng/dl and 236.4 ng/dl 4.6 8.2, respectively, in BPH and PCa. Statistically, there was an inverse correlation between testosterone and ESR2 levels in prostate cancer (p<0.05). Conclusion: This study found lower testosterone correlates with ESR2 modulation.

Molecular diagnostics of prostate cancer: impact of molecular tests.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men. Prostate-specific antigen (PSA) testing is used in screening programs for early detection with a consequent reduction of PCa-specific mortality at the cost of overdiagnosis and overtreatment of the nonaggressive PCa. Recently, several assays have been commercially developed to implement PCa diagnosis, but they have not been included in both screening and diagnosis of PCa. This review aims to describe the actual and novel commercially available molecular biomarkers that can be used in PCa management to implement and tailor the screening and diagnosis of PCa.

Comparison of serum 25-hydroxy vitamin D amongst black African prostate cancer patients with non-aggressive versus aggressive disease using the Gleason score

Background: Black men of African descent have higher risk for developing prostate cancer and present at a younger age with advanced disease and a poorer prognosis. Limited number of studies directly linking serum vitamin D with either prostate cancer prognosis or measures of prostate cancer aggressiveness have been done. The objective of this study is to compare serum 25 hydroxy vitamin D levels in patients with non-aggressive and aggressive prostate cancer using the Gleason score in black Africans in Jos. Methods: A cross sectional study conducted among fifty patients who presented to the urological surgical out-patient clinic of the Jos University Teaching Hospital who had clinical diagnosis of prostate cancer and were scheduled for prostate biopsy. Blood samples for serum 25-hydroxy vitamin D assay was analysed using the enzyme linked immunosorbent assay (ELISA) technique, patients with histologically confirmed prostate cancer were analysed. Data was collected in a proforma, statistical analysis done using statistical package for the social sciences (SPSS)(R) version 23 and t-test was used for comparison with a p value <0.05 considered significant. Results: Fifty patients were studied whose age ranged from 50-89 years. The mean level of serum 25-hydroxy vitamin D was 37.90 ng/ml±17.92. The mean serum 25-hydroxy vitamin D of patients with non-aggressive disease (GS≤6) and aggressive disease (GS≥7) was 48.44±17.09 and 34.57±17.08 respectively with a p value of 0.018. Conclusions: This study showed that black African prostate cancer patients with high grade tumors (Gleason score ≥7) had significantly lower 25-hydroxy vitamin D levels compared to those with low grade tumors (Gleason score <7).

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer

Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. To identify genes associated with aggressive PCa. A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

Prediagnostic markers of insulin resistance and prostate cancer risk and death: A pooled study.

Insulin resistance has been shown to be related to a higher risk of several cancers, but the association with prostate cancer (PCa) has been inconsistent. We investigated prediagnostic markers of insulin resistance in men in four cohorts in Sweden, in relation to PCa risk (total, non-aggressive and aggressive) and PCa death using multivariable-adjusted Cox regression. The number of men, PCa cases and PCa deaths was up to 66,668, 3940 and 473 for plasma glucose and the triglyceride-glucose (TyG) index, and up to 3898, 586 and 102 for plasma insulin, glycated haemoglobin (HbA1c) and leptin. Higher HbA1c was related to a lower risk of non-aggressive PCa but no significant associations were found for insulin resistance markers with the risk of aggressive or total PCa. In PCa cases, higher glucose and TyG index were related to a higher risk of PCa death (hazard ratio [HR] per higher standard deviation, 1.22, 95% CI 1.00-1.49 and 1.24, 95% CI 1.00-1.55), which further increased when restricting the analyses to glucose and TyG index measures taken <10 years before the PCa diagnosis (HR, 1.70, 95% CI 1.09-2.70 and 1.66, 95% CI 1.12-2.51). No associations were observed for other markers in relation to PCa death. The results of this study showed no associations of insulin resistance markers with the risk of clinically relevant PCa, but higher glucose and TyG index were associated with poorer survival from PCa. The lack of association for other insulin resistance markers may be due to their smaller sample size.

Abstract 6496: Exposure phenotype risk scores (E-PRS) and prostate cancer aggressiveness in the Michigan Genomics Initiative (MGI)

Abstract Background: Exposure phenotype risk scores (E-PRS) use genetic variation as a natural experiment to examine the causal relationship between risk or protective factors and diseases. A recent review summarized 76 studies using this approach, finding that several factors (alcohol consumption, BMI, telomere length, hormones) likely cause cancer. However, this article also highlighted the need for larger studies incorporating more, newly discovered associated, variants in the E-PRS and investigating specific cancer types vs. all cancers and cancer subtypes. Methods: We used 21 published E-PRS that were derived from summary statistics of large genome-wide association studies using PRSCS. We evaluated 15 continuous and 6 binary E-PRS for factors that are known or hypothesized to contribute to cancer risk or progression and their association with prostate cancer aggressiveness and death. Our sample included 1784 unrelated, genotyped prostate cancer patients from the Michigan Genomics Initiative (MGI). Conditional logistic regression was used to estimate these 21 E-PRS's odds ratios (OR) and their 95% confidence intervals (CI) for high- vs. low-stage, high- vs. low-grade, and aggressive (high-stage or -grade) vs. non-aggressive (low-stage and -grade) prostate cancer. Cox regression was used to evaluate the hazard ratios (HR) and their 95% CI of prostate cancer deaths by E-PRS. Lasso and Ridge regressions were used to reduce model complexity and prevent overfitting for the final E-PRS model. All multivariable models were adjusted for age, genotyping batch, recruiting study, and genetic PCs. Results: For high- vs. low-stage prostate cancer, we detected statistically significant associations with E-PRS for type 2 diabetes (per standard deviation (SD) change OR=0.86, 95% CI=0.77-0.97) and estimated glomerular filtration rate (eGFR) (per SD change OR=1.19, 95% CI=1.00-1.41). We also observed a suggestive inverse association with sleep apnea E-PRS. We observed no statistically significant associations for high- vs. low-grade prostate cancer, but there was a possible inverse association with the diastolic blood pressure (DBP) E-PRS. We noticed no statistically significant associations when comparing aggressive vs. non-aggressive prostate cancer; however, suggestive inverse associations with E-PRS for DBP and smoking were found. For prostate cancer death, we observed a statistically significant decreased risk of death with higher BMI E-PRS (per SD HR=0.29, 95% CI: 0.09 - 0.89). We also observed a suggestive inverse association with the eGFR E-PRS. Similar results were found in Lasso and Ridge regression. Conclusions: Several E-PRS were significant predictors of aggressive or fatal prostate cancer. In the future, we will test significant E-PRS from this analysis to determine whether they predict aggressiveness or mortality in newly recruited MGI prostate cancer cases in 2022. Citation Format: Xinman Zhang, Lars G. Fritsche, Bhramar Mukherjee, Alison M. Mondul. Exposure phenotype risk scores (E-PRS) and prostate cancer aggressiveness in the Michigan Genomics Initiative (MGI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6496.

Urinary PSA and Serum PSA for Aggressive Prostate Cancer Detection.

Serum PSA, together with digital rectal examination and imaging of the prostate gland, have remained the gold standard in urological practices for the management of and intervention for prostate cancer. Based on these adopted practices, the limitations of serum PSA in identifying aggressive prostate cancer has led us to evaluate whether urinary PSA levels might have any clinical utility in prostate cancer diagnosis. Utilizing the Access Hybritech PSA assay, we evaluated a total of n = 437 urine specimens from post-DRE prostate cancer patients. In our initial cohort, PSA tests from a total of one hundred and forty-six (n = 146) urine specimens were obtained from patients with aggressive (Gleason Score ≥ 8, n = 76) and non-aggressive (Gleason Score = 6, n = 70) prostate cancer. A second cohort, with a larger set of n = 291 urine samples from patients with aggressive (GS ≥ 7, n = 168) and non-aggressive (GS = 6, n = 123) prostate cancer, was also utilized in our study. Our data demonstrated that patients with aggressive disease had lower levels of urinary PSA compared to the non-aggressive patients, while the serum PSA levels were higher in patients with aggressive prostate disease. The discordance between serum and urine PSA levels was further validated by immuno-histochemistry (IHC) assay in biopsied tumors and in metastatic lesions (n = 62). Our data demonstrated that aggressive prostate cancer was negatively correlated with the PSA in prostate cancer tissues, and, unlike serum PSA, urinary PSA might serve a better surrogate for capitulating tissue milieus to detect aggressive prostate cancer. We further explored the utility of urine PSA as a cancer biomarker, either alone and in combination with serum PSA, and their ratio (serum to urine PSA) to predict disease status. Comparing the AUCs for the urine and serum PSA alone, we found that urinary PSA had a higher predictive power (AUC= 0.732) in detecting aggressive disease. Furthermore, combining the ratios between serum to urine PSA with urine and serum assay enhanced the performance (AUC = 0.811) in predicting aggressive prostate disease. These studies support the role of urinary PSA in combination with serum for detecting aggressive prostate cancer.

Developing quantitative assays for six urinary glycoproteins using parallel reaction monitoring, data-independent acquisition, and TMT-based data-dependent acquisition.

Quantitative approaches encompassing parallel reaction monitoring (PRM), data-independent acquisition (DIA), and data-dependent acquisition (DDA) are commonly used to investigate protein expression profiles. However, analytical performances of assays developed using PRM, DIA, and Tandem Mass Tag (TMT)-based DDA for quantitative proteomics have yet not been investigated. Here, we developed assays for glycopeptides identified from six glycoproteins, including Leucine-rich alpha-2-glycoprotein (LRG1), Prostaglandin-H2 D-isomerase (PTGDS), Aminopeptidase N (ANPEP), CD63 antigen (CD63), Clusterin (CLU), and Prostatic acid phosphatase (ACPP), using PRM, DDA, and DIA and evaluated the analytical performances of each assay using the different acquisition modes. We also compared assays in each acquisition mode on three different orbitrap instruments: Thermo Fisher Q Exactive, Exploris 480, and Lumos. We found that DIA showed the largest linear range, highest sensitivity, and most reproducibility. We then applied our developed DIA assays to urine samples from non-aggressive (n=48) and aggressive (n=35) prostate cancer patients. In conclusion, we developed assays for the six glycoproteins, evaluated the analytical performances of each assay in DIA, PRM, and PRM acquisition modes on three types of mass spectrometry instruments, and chose the DIA assays for the quantitative analysis of urine samples from patients with aggressive and non-aggressive prostate cancer.

Urine-derived exosomal PSMA is a promising diagnostic biomarker for the detection of prostate cancer on initial biopsy.

It is well-established that the lack of accurate diagnostic modalities for prostate cancer (PCa) leads to overdiagnosis and overtreatments. Accordingly, this study aimed to assess the value of urine-derived exosomal prostate-specific membrane antigen (PSMA) as a biomarker for the diagnosis of PCa and clinically significant prostate cancer (csPCa). A total of 284 urine samples were collected from patients after the digital rectal examination (DRE). Urinary exosomes were extracted using commercial kits, and urine-derived exosomal PSMA was determined via enzyme-linked immunosorbent assay (ELISA). Evaluation of diagnostic accuracy of PSMA was performed via receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and waterfall plots. We found that urine-derived exosomal PSMA was significantly higher in PCa and csPCa than in benign prostatic hyperplasia (BPH) and BPH + non-aggressive prostate cancer (naPCa) groups (P < 0.001). Furthermore, the urine-derived exosome PSMA yielded area under the ROC curve (AUC) values of 0.876 and 0.826 for detecting PCa and csPCa, respectively, suggesting better performance than traditional clinical biomarkers. Besides, when the cutoff value used corresponded to a sensitivity of 95%, urine-derived exosomal PSMA could avoid unnecessary biopsies in 41.2% of cases and missed only 0.7% of csPCa cases. Urine-derived exosomal PSMA exhibits a good diagnostic yield for detecting PCa and csPCa. Findings of the present study provide the foothold for future studies on cancer management and research in this patient population.

Circulating microRNA expression profiles to identify a potential link between prostate cancer and obesity

Effective diagnostic methods are needed to apply appropriate treatment strategies in patients with aggressive prostate cancer. From this point of view, risk factors that cause prostate cancer or its aggressiveness should be considered. Obesity is a critical risk factor for triggering prostate cancer's metastatic properties. microRNAs are used as biomarkers in diagnosing cancer and obesity depending on their tissue-specific expression patterns. This study investigates the role of obesity in the metastatic profile of prostate cancer depending on the differential expression signatures of selected miRNAs in prostate cancer and obese patients. The roles of miR-100, miR-141 and miR-145 in prostate cancer and obesity are partially known. However, their potential to become circular biomarkers in the blood is not elucidated. There is no previous data on miR-4463 and miR-653 on prostate cancer and obesity association. In this study, the blood samples were taken and obtained serum from 69 patients of 6 subgroups that consisted of one healthy group and five unhealthy groups based on their different prostate cancer or obesity levels. Five selected miRNA expression analyses (miR-100, miR-141, miR-145, miR-4463, and miR-653) were performed through total RNA isolation, which was confirmed via synthetic cel-miR-39 miRNA. Quantitative Real-Time PCR analyzed the expression levels of selected miRNAs. Data analysis was performed via normalising target miRNA expression levels with cel-miR-39. In this study, we found that the relationship between prostate cancer and obesity was investigated at the molecular level. It was suggested that target miR-100 could be a promising biomarker for non-obese and aggressive prostate cancer patients. miR-145 is a more potential biomarker than miR-141 for non-aggressive and non-obese patients. miR-4463 can be used to predict more prostate cancer patients than obese patients. Lastly, miR-653 can be a biomarker for non-aggressive prostate cancer cells.

Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations.

We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program and additional independent studies. Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population. The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8794 cases, 55,657 controls), and Hispanic (1082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI = 3.62-3.96), 2.8-fold in African ancestry men (95% CI = 2.59-3.03), and 3.2-fold in Hispanic men (95% CI = 2.64-3.92). The PRS did not discriminate risk of aggressive versus nonaggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR = 7.11; 55-60 years, OR = 4.26; >70 years, OR = 2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40-60% PRS category. Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine whether the PRS could be used for risk-stratified screening and early detection. This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Abstract LB159: Neighborhood obesogenic environment and risk of prostate cancer: The Multiethnic Cohort

Abstract Background: Obesity is associated with risk of aggressive prostate cancer. It is not known whether neighborhood obesogenic factors are associated with prostate cancer risk. Methods: Neighborhood socioeconomic status (nSES) and four neighborhood obesogenic environment factors (urbanicity, mixed-land development, unhealthy food environment, and parks) were assessed for associations with prostate cancer risk among 41,563 African American, European American, Japanese American, and Latino males in the Multiethnic Cohort Study (MEC), California site. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for non-aggressive and aggressive prostate cancer, adjusting for individual-level sociodemographic, behavioral, and prostate cancer risk factors. Analyses were stratified by race, ethnicity, and, among Latino males, nativity. Results: Males residing in low SES, compared to high SES, neighborhoods had lower risk of non-aggressive prostate cancer (lowest vs. highest quintile HR=0.81; 95% CI=0.68, 0.95, p-trend 0.024); driven by a similar trend among U.S.-born and foreign-born Latino males. Foreign-born Latino males in neighborhoods with low mixed-land development had increased risk (lowest vs. highest quintile HR=1.52; 95% CI=1.09, 2.12). African American males in neighborhoods with more unhealthy food environments had increased risk of aggressive disease (more vs. none, HR=1.35; 95% CI=1.02, 1.77). Conclusions: Neighborhood SES and obesogenic factors were independently associated with prostate cancer risk; associations varied by race, ethnicity, nativity, and disease aggressiveness. Impact: Upstream structural and social determinants of health that contribute to neighborhood obesogenic characteristics likely impact prostate cancer risk differently across groups defined by race, ethnicity, and nativity and by disease aggressiveness. Citation Format: Mindy C. Hebert-DeRouen, Li Tao, Salma Shariff-Marco, Juan Yan, Yurii B. Shvetsov, Song-Yi Park, Cheryl L. Albright, Kristine Monroe, Loic Le Marchand, Lynne Wilkens, Scarlett L. Gomez, Iona Cheng. Neighborhood obesogenic environment and risk of prostate cancer: The Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB159.

Abstract 688: Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases

Abstract Rare pathogenic variants in DNA repair genes have been found to influence risk of aggressive prostate cancer. We conducted a large case-only exome sequencing study to further understand the role of rare coding variation in aggressive prostate cancer in a study of 9,185 aggressive (prostate cancer death, metastatic disease, T4, or both T3 and Gleason≥8) and 8,361 non-aggressive cases (T1/T2 and Gleason≤6) of European ancestry from 19 international studies. Stage 1 samples (N=5,545) had whole exome-sequencing, and stage 2 samples (N=12,001) had targeted exome sequencing for 1,459 genes selected based on stage 1 results and previous evidence. Logistic regression models were used to evaluate gene-based tests and the aggregate effect of multiple genes to investigate whether carrying pathogenic/likely pathogenic/deleterious (P/LP/D) variants (18,759 identified) was associated with risk of aggressive prostate cancer, prostate cancer death (N=6,033), or metastatic disease (N=1,730) compared to non-aggressive disease. Gene-based tests were meta-analyzed across stages 1 and 2. BRCA2, ATM, and NBN had the most statistically significant gene-based results: BRCA2 P/LP/D variant carriers had 4.3-fold higher odds of aggressive disease (95% CI=3.15-5.86, P=4x10-20), 4.7-fold higher odds of prostate cancer death (95% CI=3.41-6.59, P=2x10-20), and 5.7-fold higher odds of metastatic disease (95% CI=3.71-8.76, P=2x10-15); ATM P/LP/D variant carriers had 2.2-fold higher odds of aggressive disease (95% CI=1.58-2.99, P=2x10-6), 2.2-fold higher odds of prostate cancer death (95% CI=1.52-3.05, P=2x10-5), and 3.0-fold higher odds of metastatic disease (95% CI=1.93-4.61, P=9x10-7); and NBN P/LP/D variant carriers had 5.9-fold higher odds of metastatic disease (95% CI=2.56-13.84, P=3x10-5). Among potentially novel genes with strong but not exome-wide significant statistical evidence were MMP19, involved in reproduction and metastasis, with carriers having 2.8-fold higher odds of prostate cancer death (95% CI=1.53-5.05, P=8x10-4); PKD2L2, involved in fertility, with carriers having 3.5-fold higher odds of prostate cancer death (95% CI=1.76-7.04, P=5x10-4); and SMPD1, involved in converting sphingomyelin to ceramide, with carriers having 5.3-fold higher odds of metastatic disease (95% CI=1.85-14.98, P=0.002). At least one P/LP/D variant within a subset of 24 previously curated candidate prostate cancer DNA repair genes was carried by 12.8% of aggressive cases (OR=1.48, 95% CI=1.34-1.64, P=3x10-14), 12.6% of cases who died due to prostate cancer (OR=1.47, 95% CI=1.31-1.65, P=3x10-11), and 15.1% of metastatic cases (OR=2.16, 95% CI=1.57-2.16, P=5x10-14) compared to 9.4% of non-aggressive cases. These findings support the importance of rare genetic variation in aggressive prostate cancer risk and may have important implications for prostate cancer risk stratification and screening. Citation Format: Burcu F. Darst, Ed Saunders, Tokhir Dadaev, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y. Xia, Stephen Chanock, Sonja I. Berndt, Susan M. Gapstur, Victoria Stevens, Demetrius Albanes, Stephanie J. Weinstein, Vincent Gnanapragasam, Graham G. Giles, Tu Nguyen-Dumont, Roger L. Milne, Mark M. Pomerantz, Julie A. Schmidt, Ruth C. Travis, Timothy J. Key, Konrad H. Stopsack, Lorelei A. Mucci, William J. Catalona, Beth Marosy, Kurt N. Hetrick, Kimberly F. Doheny, Robert J. MacInnis, Melissa C. Southey, Rosalind A. Eeles, Fredrik Wiklund, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 688.

Intake Patterns of Specific Alcoholic Beverages by Prostate Cancer Status.

Simple SummaryPrevious studies have shown heavy intake of different alcoholic beverages affects prostate cancer (PCa) clinical outcomes differently. However, the intake patterns of specific alcoholic beverages for PCa status are understudied. The study’s objective is to evaluate intake patterns of total alcohol and three types of alcoholic beverage (beer, wine, and spirits) by PCa risk and aggressiveness status. This study included 10,029 men with European ancestry (4676 non-PCa men and 5353 PCa patients). We found PCa patients had a similar total heavy alcohol intake compared with non-PCa men. However, PCa patients were likely to drink more wine and spirits than non-PCa men. Patients with aggressive PCa drank more beer but not wine and spirits. Interestingly, heavy wine intake was inversely associated with PCa aggressiveness. These findings suggest that the intake patterns of specific alcoholic beverages differ by PCa status, and this information might help develop personalized alcohol intervention for PCa patients.Background: Previous studies have shown that different alcoholic beverage types impact prostate cancer (PCa) clinical outcomes differently. However, intake patterns of specific alcoholic beverages for PCa status are understudied. The study’s objective is to evaluate intake patterns of total alcohol and the three types of beverage (beer, wine, and spirits) by the PCa risk and aggressiveness status. Method: This is a cross-sectional study using 10,029 men (4676 non-PCa men and 5353 PCa patients) with European ancestry from the PCa consortium. Associations between PCa status and alcohol intake patterns (infrequent, light/moderate, and heavy) were tested using multinomial logistic regressions. Results: Intake frequency patterns of total alcohol were similar for non-PCa men and PCa patients after adjusting for demographic and other factors. However, PCa patients were more likely to drink wine (light/moderate, OR = 1.11, p = 0.018) and spirits (light/moderate, OR = 1.14, p = 0.003; and heavy, OR = 1.34, p = 0.04) than non-PCa men. Patients with aggressive PCa drank more beer than patients with non-aggressive PCa (heavy, OR = 1.48, p = 0.013). Interestingly, heavy wine intake was inversely associated with PCa aggressiveness (OR = 0.56, p = 0.009). Conclusions: The intake patterns of some alcoholic beverage types differed by PCa status. Our findings can provide valuable information for developing custom alcohol interventions for PCa patients.

Associations Between Vertebral Marrow Proton Density Fat Fraction and Risk of Prostate Cancer.

Bone marrow adipocytes may be responsible for cancer progression. Although marrow adipogenesis is suspected to be involved in prostate carcinogenesis, an association between marrow adiposity and prostate cancer risk has not been clearly established in vivo. This work included 115 newly diagnosed cases of histologically confirmed prostate cancer (range, 48–79 years) and 87 age-matched healthy controls. Marrow proton density fat fraction (PDFF) was measured by 3.0-T MR spectroscopy at the spine lumbar. Associations between marrow PDFF and risk of prostate cancer by stage of disease and grade sub-types were performed using multivariable polytomous logistic regression. There were no significant group differences in the vertebral marrow PDFF, despite prostate cancer patients having 6.6% higher marrow PDFF compared to the healthy controls (61.7 ± 9.8% vs. 57.9 ± 6.5%; t = 1.429, p = 0.161). After adjusting for various clinical and demographic characteristics, we found that elevated marrow PDFF was related to an increased risk of high-grade prostate cancer [odds ratios (OR) = 1.31; 95% confidence interval (CI), 1.08–1.57; p = 0.003]. Likewise, increased marrow PDFF had a significantly positive correlation with aggressive prostate cancer risk (OR = 1.54; 95% CI, 1.13–1.92; p <0.001). There were no associations between marrow PDFF and low-grade (p = 0.314) or non-aggressive (p = 0.435) prostate cancer risk. The data support the hypothesis that marrow adiposity was correlated with increased risk of aggressive prostate cancer, supporting a link between adipogenesis and prostate cancer risk.

Neighborhood Obesogenic Environment and Risk of Prostate Cancer: The Multiethnic Cohort.

Obesity is associated with risk of aggressive prostate cancer. It is not known whether neighborhood obesogenic factors are independently associated with prostate cancer risk. Neighborhood socioeconomic status (nSES) and four neighborhood obesogenic environment factors (urbanicity, mixed-land development, unhealthy food environment, and parks) were assessed for associations with prostate cancer risk among 41,563 African American, Japanese American, Latino, and White males in the Multiethnic Cohort (MEC) Study, California site. Multivariable Cox proportional hazards regression was used to estimate HRs and 95% confidence intervals (CI) for nonaggressive and aggressive prostate cancer, adjusting for individual-level sociodemographic, behavioral, and prostate cancer risk factors. Analyses were stratified by race, ethnicity, and, among Latino males, nativity. Males residing in low-SES, compared with high-SES, neighborhoods had lower risk of nonaggressive prostate cancer [lowest vs. highest quintile HR = 0.81; 95% confidence interval (CI) = 0.68-0.95, Ptrend 0.024], driven by a similar trend among foreign-born Latino males. Foreign-born Latino males in neighborhoods with low mixed-land development had increased risk of non-aggressive disease (lowest vs. highest quintile HR = 1.49; 95% CI = 1.07-2.09). For aggressive disease, the only association noted was between lower mixed-land development and lower risk among White males (Ptrend = 0.040). nSES and obesogenic environment factors were independently associated with prostate cancer risk; associations varied by race, ethnicity, nativity, and disease aggressiveness. Upstream structural and social determinants of health that contribute to neighborhood obesogenic characteristics likely impact prostate cancer risk differently across groups defined by race, ethnicity, and nativity and by disease aggressiveness.

Biomarkers of Glucose Homeostasis and Inflammation with Risk of Prostate Cancer: A Case–Cohort Study

AbstractBackground:Few prospective studies have examined biomarkers of glucose homeostasis or inflammation with prostate cancer risk by tumor stage or grade.Methods:We conducted a case–cohort study to examine associations of prediagnosis hemoglobin A1c (HbA1c), C-peptide, and C-reactive protein (CRP) with prostate cancer risk overall and stratified by tumor stage and grade. The study included 390 nonaggressive (T1–2, N0, M0, and Gleason score &amp;lt;8) and 313 aggressive cases (T3–4, or N1, or M1, or Gleason score 8–10) diagnosed after blood draw (1998–2001) and up to 2013, and a random subcohort of 1,303 cancer-free men at blood draw in the Cancer Prevention Study-II Nutrition Cohort. Prentice-weighted Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI).Results:In the multivariable-adjusted model without body mass index, HbA1c was inversely associated with nonaggressive prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00; P = 0.04). Analyses stratified by tumor stage and grade separately showed that HbA1c was inversely associated with low-grade prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80–1.00) and positively associated with high-grade prostate cancer (HR per unit increase, 1.15; 95% CI, 1.01–1.30). C-peptide and CRP were not associated with prostate cancer overall or by stage or grade.Conclusions:The current study suggests that associations of hyperglycemia with prostate cancer may differ by tumor grade and stage.Impact:Future studies need to examine prostate cancer by tumor stage and grade, and to better understand the role of hyperglycemia in prostate cancer progression.

Abstract PO-126: Identification of distinct mRNA &amp; microRNA signatures and mRNA-miRNA pairs associated with inter-ethnic differences in prostate cancer aggressiveness

Abstract Introduction: The incidence of aggressive prostate cancer (PCa) and mortality is disproportionately higher in men of African-American (AA) ancestry. Treatment options for these patients are docetaxel or cabazitaxel alone or in combination with bevacizumab, thalidomide, and prednisone or immunotherapy. However, these chemotherapeutics typically only improve survival slightly (3-4 months). Further, majority of patients develop metastatic PCa over time, resistant to conventional chemotherapy (metastatic castration resistance PCa or mCRPC). Therefore, an understanding of the molecular mechanisms underlying the ethnic differences in disease aggressiveness and progression in PCa is needed. Methods: In this study, we performed mRNA and miRNA expression (RNAseq) analysis on PCa cell lines representing different tumor types (aggressive androgen receptor (AR) nonresponsive AR- vs. non-aggressive AR+) and derived from patients with European American/EA (PC3, PC3M, DU145, DUTXR, 22RV1, LNCaP, VCaP, LaPC4, C4, C4-2B) and AA (MDA-Pca-2b, RC77, RC165, RC43) ancestry to identify differentially expressed genes (DEG) associated with tumor aggressiveness and ethnicity. Next, we validated the top DEG signatures using an AA vs EA patient cohort dataset as well as in silico validation using The Cancer Genome Atlas (TCGA) database. For each miRNA, functional analysis was performed using miRBase datasets and mRNA-miRNA pairs and binding sites were predicted by TargetScan. Finally, IPA (Ingenuity Pathway Analysis) was performed to identify key regulators and downstream effects on biological and disease processes based on the expression patterns of DEGs. Results: We identified distinct mRNA and miRNA expression signatures associated with aggressive vs. non-aggressive PCa of EA vs. AA origin. The top DEGs that were associated with patient survival (p&amp;lt; 0.0001), stratified by Gleason scores, were PLAU, TGFB1, SERPINE1, MET, TIPM1, ITGA3, SERPINB5, PLAUR, MMPs, CDKN1A, and IGF1. The transporter genes SLC25A, SLC16A, and ABCB6 were also identified as important markers of aggressiveness. Notably, PLAU, MCAM, MET, TIMP1 were top DEGs in AA vs EA cell lines while SERPINE1 and MCAM were DEGs in AA vs EA patient cohort. IPA identified the activation of the angiogenesis pathway as a crucial factor for cancer aggressiveness. Top predicted miRNA-mRNA pairs included SERPINE1-let7, PLAU- mir181 which potentially influence differential gene expression in late-stage cancers. Finally, our immunoblotting results confirmed the protein expression changes of top DEGs. Next, we plan to perform CRISPR-based gene editing to functionally validate the molecular (mRNA/miRNA) signatures. Conclusion: An -omics-based approach was used to identify genetic signatures that provide insights into the molecular basis of PCa aggressiveness between men of EA vs AA ancestry. We believe this strategy will aid in developing effective targeted ethnicity-specific personalized treatment schedules for aggressive forms of PCa. This promises to address the known health disparity that is observed in AA men. Citation Format: Taraswi Mitra Ghosh, Jason White, Suman Mazumder, Joshua Davis, Grace Hurley, Brian Cummings, Gary Piazza, Amit K Mitra, Clayton Yates, Robert Arnold. Identification of distinct mRNA &amp; microRNA signatures and mRNA-miRNA pairs associated with inter-ethnic differences in prostate cancer aggressiveness [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-126.

Epigenome-Wide Association Study of Prostate Cancer in African Americans Identifies DNA Methylation Biomarkers for Aggressive Disease.

DNA methylation plays important roles in prostate cancer (PCa) development and progression. African American men have higher incidence and mortality rates of PCa than other racial groups in U.S. The goal of this study was to identify differentially methylated CpG sites and genes between clinically defined aggressive and nonaggressive PCa in African Americans. We performed genome-wide DNA methylation profiling in leukocyte DNA from 280 African American PCa patients using Illumina MethylationEPIC array that contains about 860K CpG sties. There was a slight increase of overall methylation level (mean β value) with the increasing Gleason scores (GS = 6, GS = 7, GS ≥ 8, P for trend = 0.002). There were 78 differentially methylated CpG sites with P < 10−4 and 9 sites with P < 10−5 in the trend test. We also found 77 differentially methylated regions/genes (DMRs), including 10 homeobox genes and six zinc finger protein genes. A gene ontology (GO) molecular pathway enrichment analysis of these 77 DMRs found that the main enriched pathway was DNA-binding transcriptional factor activity. A few representative DMRs include HOXD8, SOX11, ZNF-471, and ZNF-577. Our study suggests that leukocyte DNA methylation may be valuable biomarkers for aggressive PCa and the identified differentially methylated genes provide biological insights into the modulation of immune response by aggressive PCa.