Background: In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research. Methods: Among prostate cancer cases diagnosed in 2007 in the National Cancer Institute’s Surveillance, Epidemiology, and End Results-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV). Results: In our case population (n = 55 900), 3073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM staging and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of category T4 or N1 or M1 or Gleason score of 8 or greater prostate cancer, because this definition had one of the higher PPVs (0.23, 95% confidence interval = 0.22 to 0.24) and reasonable sensitivity (0.66, 95% confidence interval = 0.64 to 0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses. Conclusions: We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced category (T4 or N1 or M1), high-grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

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 P_trend < .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 (P_interaction = .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.

Early-onset prostate cancer is often more aggressive and may have a different aetiology than later-onset prostate cancer, but has been relatively little studied to date. We evaluated occupation in relation to early- and later-onset prostate cancer in a large pooled study. We used occupational information from census data in five Nordic countries from 1960 to 1990. We identified prostate cancer cases diagnosed from 1961 to 2005 by linkage of census information to national cancer registries and calculated standardised incidence ratios (SIRs) separately for men aged 30-49 and those aged 50 or older. We also conducted separate analyses by period of follow-up, 1961-1985 and 1986-2005, corresponding to pre- and post-prostate-specific antigen (PSA) screening. For early-onset prostate cancer (n = 1521), we observed the highest SIRs for public safety workers (e.g. firefighters) (SIR = 1.71, 95% confidence interval [CI]: 1.23-2.31) and military personnel (SIR = 1.97, 95% CI: 1.31-2.85). These SIRs were significantly higher than the SIRs for later-onset disease (for public safety workers, SIR = 1.10, 95% CI: 1.07-1.14 and for military personnel, SIR = 1.09, 95% CI: 1.05-1.13; p_{heterogeneity} = 0.005 and 0.002, respectively). Administrators and technical workers also demonstrated significantly increased risks for early-onset prostate cancer, but the SIRs did not differ from those of later-onset disease (p_{heterogeneity} >0.05). While our early-onset finding for public safety workers was restricted to the post-PSA period, that for military personnel was restricted to the pre-PSA period. Our results suggest that occupational exposures, particularly for military personnel, may be associated with early-onset prostate cancer. Further evaluation is needed to explain these findings.

Chromosome 8q24 has emerged as an important genetic susceptibility region for several cancers, including prostate cancer; however, little is known about the contribution of DNA methylation in this region to risk. We prospectively evaluated DNA methylation at 8q24 in relation to prostate cancer using pre-diagnostic blood samples from 694 prostate cancer cases (including 172 aggressive cases) and 703 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We used logistic regression to estimate odds ratios and 95% confidence intervals. Although none remained significant after adjustment for multiple testing (q>0.05), of the 50 CpG sites meeting quality control, we identified 8 sites that were nominally associated with prostate cancer (Ptrend<0.05), including 6 correlated (Spearman ρ: 0.20-0.52) sites in POU5F1B and 2 intergenic sites (most significant site: Chr8:128428897 in POU5F1B, Ptrend=0.01). We also identified two correlated (ρ=0.39) sites in MYC (Chr8:128753187 and Chr8:128753154) that were associated with aggressive (Ptrend=0.02 and 0.03), but not non-aggressive disease (Ptrend=0.70 and 0.20; Pheterogeneity=0.01 and 4.6 × 10-3). These findings persisted after adjustment for the top 8q24 prostate cancer variants in our study. Although requiring replication, our findings provide some evidence that 8q24 DNA methylation levels may be associated with prostate cancer risk.

Importance: African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations.Objective: To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes.Design, Setting, and Participants: This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024.Exposures: Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants’ addresses. Self-reported race was determined using electronic medical records.Main Outcomes and Measures: A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included.Results: A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (β = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6, were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, β = 0.008; SE, 0.003; P = .01; q value = .21).Conclusions and Relevance: In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.