Abstract A036: Engaging African American men as citizen scientist to validate a prostate cancer biomarker

Cancer disparities represent a significant public health problem in the United States. Inequity in cancer screening, incidence, treatment, prognosis, and mortality is a hallmark of many common cancers ([1][1]). These disparities exist across groups defined by race, ethnicity, gender, age, and

Haitian (HA) and African American (AA) men have the highest prostate cancer (PCa) and colorectal cancer (CRC) age-adjusted mortality rates compared with other racial/ethnic groups worldwide. One contributing factor to mortality differences is that a low percentage of age-eligible HA and AA men screen for PCa and CRC, even when healthcare access and insurance are available. Reasons for cancer screening disparities may be differences in knowledge, preferences and willingness in HA and AA men. However, limited information exists on whether HA and AA men are knowledgeable about and are willing to be screened for PCa and CRC. Moreover, understanding preferences and willingness of HA and AA men to use cancer screening tests completed at home is of paramount importance given the current pandemic. We used a cross-sectional study design to assess HA and AA men’s knowledge, preferences and willingness to use at-home PCa and CRC screening tests. Survey items were developed from existing surveys assessing CRC knowledge and willingness to screen. Institutional Review Board approval was obtained to invite persons who identified as male, at least 18 years of age and Black (as either AA and/or HA) to complete the survey. A total of 36 Black men completed the survey; 42% self-identified as both ‘African American’ and ‘Haitian’ (AA/HA), 44% identified only as AA, and 14% identified only as HA. Regardless of race or ethnicity, 75% of all participants were 45 years or younger (range: 18–85). Although more than 80% of all participants heard about PCa and CRC, only 50% of participants aged at least 50 years old were screened for CRC. The majority of participants (AA/HA = 67%; HA = 80%; AA = 56%) were unaware of at-home CRC screening tests; however, 80% of AA/HA men and 60% of HA men were willing to use an at-home CRC screening test compared to 44% of AA men.

Background: African American (AA) men have the highest mortality rate from prostate cancer compared to men from other races. Differences in the spectrum of somatic genomic alterations in tumors between AA men differs from non-AA men has not been well characterized as relatively few AA men have been included in prostate cancer genomic studies. To address this, we examined 5 publicly-available and commercial genomic datasets containing AA men with prostate cancer to identify novel alterations associated with race. Methods: In a meta-analysis of 4 public datasets, we investigated the mutational frequencies of 14 genes across 252 AA men and 635 non-AA men with primary prostate cancer. We also examined genomic alterations from the tumors of 436 AA men and 3018 EA men with primary or metastatic prostate cancer using the Foundation One assay. Results: We identified mutations in ZFHX3 and focal deletions in ETV3 more frequently in tumors from AA patients. The mutational frequency of TP53 was strongly associated with increasing Gleason grade. Using the commercial assay, we identified alterations in PTEN and TMPRSS2-ERG as less frequent in AA patients compared to non-AA patients in both primary and metastatic tumors. MYC amplifications were more frequent in AA patients with metastatic prostate cancer. Furthermore, we found that genomic alterations in KMT2D and CCND1 were more frequent in primary prostate tumors from AA patients, resulting in differential cell cycle genes and KMT alterations. MYC amplifications were more frequent in AA patients with metastatic prostate cancer. Genomic alterations in DNA repair genes were found at similar frequencies between EA and AA patients. Conclusion: While these results indicate that differences in mutational profiles may exist between racial groups in prostate cancers, additional sequencing studies that profile AA and EA men from the same clinical setting and that are matched for clinical covariates may be needed to confirm these findings. Overall, these results have implications for applying precision cancer medicine in AA prostate cancer patients. Citation Format: Yusuke Koga, Hanbing Song, Zachary Chalmers, Justin Newberg, Garrett Frampton, Joshua Campbell, Franklin Huang. Similarities and differences between genomic profiles of prostate cancers from African American and European American men with implications for precision cancer medicine [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D120.

Racial disparities in prostate cancer care: Is adherence to National Comprehensive Cancer Network guidelines good enough for our patients?

PD11-04 THE LIMITED UTILITY OF PROSTATE HEALTH INDEX IN AFRICAN AMERICAN MEN WITH A PSA 4-10

In the United States, African American (AA) men are at 60% higher risk of developing prostate cancer than European American (EA) men, and AA men are 2.4 times more likely to die from prostate cancer than EA men. Although these disparities are frequently attributed to the greater aggressiveness of prostate cancer among AA men, it is not known what causes that prostate cancer aggressiveness in AA men. To identify germline genetic variation that could explain some of this disparity, our previous admixture mapping study identified a novel region on chromosome 7q31-34 where local ancestry was associated with risk of disease. The main objective of this study is to investigate whether candidate genes in this gene region show differences in protein product expression by cell line origin (AA vs. EA) and by cell line metastatic potential. We specifically examined the expression of three proteins sourced from this gene region through immunoblot analysis, filamin C (FLNC), glutamate receptor metabotropic B (GRM8), and cadherin-like and PC-esterase domain containing 1 (CPED1). The cell lines DU-145, PC3, LNCaP, RWPE1, and WPE1 were derived from biological specimens from EA men, whereas the PCa2b and the RC77T cell lines were sourced from AA men. The RWPE1 and WPE1 cell lines were derived from normal prostate cells, while the remaining cell lines were derived from metastatic prostate cancers. Using immunoblot analysis, we found that GRM8 is expressed at higher levels in the cell lines derived from AA men with prostate cancer compared to those from EA men with prostate cancer. In contrast, FLNC and CPED1 are expressed at higher levels in the cell lines from EA men with prostate cancer compared to those from AA men with prostate cancer. Interestingly, both FLNC and CPED1 expression is also low in the androgen sensitive LNCaP cell line. Importantly, these results are consistent with our fine mapping results in AA men, where the SNP with greatest evidence for association is located. Further, previous studies have demonstrated that the methylation status and mRNA expression of CPED1 and FLNC differed between prostate cancers from AA and EA men. Taken together, these results provide us with a foundation to test the relevance of these genes in prostate cancer growth and metastasis and contribute to our understanding of the molecular differences in prostate cancer between EA and AA men. Citation Format: Casey Wizner, Julie Ruterbusch, Nicole Kubinec, Gregory Dyson, Albert Levin, Julie Boerner, Cathryn Bock. Determination of protein expression of candidate prostate cancer genes from a novel region on chromosome 7 identified in African American men. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B33.

African American men have the highest rates of prostate cancer incidence and mortality in the United States. Understanding underlying reasons for this disparity could identify preventive interventions important to African American men. To determine whether the association of obesity with prostate cancer risk differs between African American and non-Hispanic white men and whether obesity modifies the excess risk associated with African American race. Prospective study of 3398 African American and 22,673 non-Hispanic white men who participated in the Selenium and Vitamin E Cancer Prevention Trial (2001-2011) with present analyses completed in 2014. Total, low-grade (Gleason score <7), and high-grade (Gleason score ≥7) prostate cancer incidence. With a median (interquartile range) follow-up of 5.6 (1.8) years, there were 270, 148, and 88 cases of total, low-, and high-grade prostate cancers among African American men and a corresponding 1453, 898, and 441 cases in non-Hispanic white men, respectively. Although not associated with risk among non-Hispanic white men, BMI was positively associated with an increase in risk among African American men (BMI, <25 vs ≥35: hazard ratio [HR], 1.49 [95% CI, 0.95, 2.34]; P for trend = .03). Consequently, the risk associated with African American race increased from 28% (HR, 1.28 [95% CI, 0.91-1.80]) among men with BMI less than 25 to 103% (HR, 2.03 [95% CI, 1.38-2.98]) among African American men with BMI at least 35 (P for trend = .03). Body mass index was inversely associated with low-grade prostate cancer risk within non-Hispanic white men (BMI, <25 vs ≥35: HR, 0.80 [95% CI, 0.58-1.09]; P for trend = .02) but positively associated with risk within African American men (BMI, <25 vs ≥35: HR, 2.22 [95% CI, 1.17-4.21]; P for trend = .05). Body mass index was positively associated with risk of high-grade prostate cancer in both non-Hispanic white men (BMI, <25 vs ≥35: HR, 1.33 [95% CI, 0.90-1.97]; P for trend = .01) and African American men, although the increase may be larger within African American men, albeit the racial interaction was not statistically significant (BMI, <25 vs ≥35: HR, 1.81 [95% CI, 0.79-4.11]; P for trend = .02). Obesity is more strongly associated with increased prostate cancer risk among African American than non-Hispanic white men and reducing obesity among African American men could reduce the racial disparity in cancer incidence. Additional research is needed to elucidate the mechanisms underlying the differential effects of obesity in African American and non-Hispanic white men.

Background: A diagnosis of hypertension (HTN) has been reported to be associated with an increased risk of total and aggressive prostate cancer (PCa) in some studies. In this study, we evaluated the association between HTN and total and lethal PCa in African-American (AA) and Caucasian-American (CA) men. Given that AA men are disproportionately burdened by both HTN and PCa, especially aggressive disease, we hypothesized that the positive association between HTN and total and lethal PCa is stronger in AA than CA men. We alternatively hypothesized that the positive association between HTN and PCa is the same in AA and CA men, but the higher HTN prevalence in AA men results in a greater PCa burden in AA men. Methods: We studied 1,590 AA men and 5,094 CA men from the Atherosclerosis Risk in Communities (ARIC) study without a history of cancer at the first study visit (1987-1989) and who were followed through 2012. HTN was defined based on clinic-measured systolic and diastolic blood pressure and self-reported use of antihypertensive drugs at Visit 1. First primary total PCa (N=266 in AA men, 565 in CA men) and lethal PCa (metastatic at baseline or progressed to death from prostate cancer, N=39 in AA men, 59 in CA men) were ascertained by cancer registry linkage, medical records, and death certificates. We used Cox proportional hazards regression to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of total and lethal PCa comparing CA men with HTN, AA men without HTN, and AA men with HTN to CA men without HTN. We adjusted for age, education, and purported risk factors including body mass index, waist to hip ratio, smoking, physical activity, diabetes, cholesterol-lowering medication use, and aspirin use. Results: AA men had a higher prevalence of HTN (54.6%) than CA men (28.6%) at baseline. Compared with CA men without HTN, CA men with HTN had a higher risk of total PCa (HR=1.23, 95% CI=1.01-1.49, p=0.040), and as expected, AA men without HTN had an elevated PCa risk (HR=2.41, 95% CI=1.94-3.01, p&amp;lt;0.001), but AA men with HTN had a similarly elevated PCa risk (HR=2.41, 95% CI=1.93-3.01, p&amp;lt;0.001). Patterns were similar for lethal PCa (versus CA men without HTN, CA men with HTN - HR=1.48, 95% CI=0.83-2.63, p=0.183, AA men without HTN - HR=3.27, 95% CI=1.79-5.95, p&amp;lt;0.001, AA men with HTN - HR=2.49, 95% CI=1.31-4.73, p=0.005). Conclusions: Our prospective findings support some prior studies that HTN is associated with an increased risk of total and possibly lethal PCa in CA men. Counter to our hypothesis, HTN was not associated with total or lethal PCa in AA men. Support: NHLBI, NCI, NPCR, UMMC Office of Research. Citation Format: Wanmei Wang, Eldrin Bhanat, Kenneth R. Butler, Corinne E. Joshu, Thomas H. Mosley, Elizabeth A. Platz, Christian R. Gomez. Association between hypertension and prostate cancer risk in black and white men in the Atherosclerosis Risk in Communities (ARIC) study [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C090.

6517 Background: Prostate cancer causes a disproportionate burden to AA men, and AA men are less likely than CA men to receive aggressive treatment. This is the first study to examine factors influencing treatment decision-making of AA vs. CA men in a population-based cohort. Methods: 1171 men were enrolled soon after diagnosis and before treatment through Rapid Case Ascertainment of the North Carolina state cancer registry. Researchers asked patients regarding their priorities in treatment decision-making and information sources. Differences in AA and CA men were compared using the chi-square test. Results: The most important factor for both AA and CA men was curing cancer, and preserving QOL was second most important. However, AA men were more concerned about additional factors including impact on daily activities (74% very important AA vs 58% CA for intermediate/high risk disease), recovery time (81% vs 50%), cost (66% vs 32%) and treatment time (76% vs 39%) (p &lt; .001 for each item). The most important source of information impacting treatment decisions for CA men were physician recommendations (61%), personal research (32%) and family/friend opinion (7%); for AA men, the corresponding numbers were 50%, 32% and 19%. Conclusions: AA and CA men with prostate cancer are both concerned about curing cancer, but AA men are more likely to consider multiple other social and personal factors as important in their decision-making process. Improved understanding of these differences may provide opportunities to address racial disparities in prostate cancer. [Table: see text]

Background: Obesity is a cancer risk factor. Although it does not increase the risk of localized prostate cancer, it raises the risk of the aggressive disease in men of European ancestry. Few studies investigated obesity as a prostate cancer risk factor in men of African ancestry. Findings from those studies were heterogeneous, but some reported an association of excess body fatness with aggressive disease.Methods: We examined the relationship of body mass index (BMI), waist circumference, and waist-hip ratio with prostate cancer in African American (AA) and European American (EA) men in the NCI-Maryland Prostate Cancer Case-Control Study consisting of 798 men with incident prostate cancer (402 AA and 496 EA) and 1,008 population-based controls (474 AA and 534 EA). BMI was self-reported. Waist circumference and waist-hip ratio were calculated from measurements at enrollment.Results: A high BMI either at enrollment or years prior to it was associated with a decreased risk of prostate cancer in AA men. In contrast, an elevated BMI tended to increase the disease risk in EA men. Waist circumference was inversely associated with prostate cancer in both AA and EA men, whereas a high waist-hip ratio did not associate with prostate cancer in AA men but tended to be associated with advanced/aggressive disease in EA men.Conclusions: Our findings reveal an obesity paradox among AA men in this study population, where a high BMI and waist circumference associated with a decreased disease risk.Impact: Our observations expand the knowledge of how obesity may affect prostate cancer risks in AAs. Cancer Epidemiol Biomarkers Prev; 27(8); 936-44. ©2018 AACR.

Background: Disparities in prostate cancer (PrCa) incidence and mortality between African American (AA) and European American (EA) men are partially mediated by underlying disease biology. The goal of this study was to determine how DNA methylation and transcriptomic changes drive PrCa health disparities in AA men. Methods: Transcriptomic alterations potentially mediated by DNA methylation were identified by Illumina arrays and RNA-sequencing in PrCa from 30 AA and 32 EA men. Androgen receptor (AR) protein expression was measured using tissues microarray of matched PrCa tissues from 95 EA and 92 AA men. In vitro, MDA PCa 2a (2a)/MDA PCa 2b (2b) cells derived from an AA man and LNCaP/LaPC-4 cells derived from EA men were stimulated with ionomycin, a calcium ionophore to measure intracellular calcium using fluorescent-based live imaging. Results: Unsupervised hierarchical clustering revealed DNA methylation clusters (Cluster A and Cluster B) with differential methylation of loci that regulate intracellular calcium levels including RYR2, TRPC6, and TRPA1. Increased methylation of calcium regulatory genes in Cluster A was associated with reduced disease-free time (DFT) (21.65 vs 46.71 months, p&amp;lt;0.05) only in AA men with PrCa. RYR2 (-0.122 vs -0.004, p=0.69), TRPC6 (0.006 vs -0.639, p=0.06) and TRPA1 (-0.070 vs -0.269, p&amp;lt;0.05) transcript levels were lower in Cluster A compared to Cluster B. These data suggest DNA methylation can regulate expression of calcium regulating genes. In vitro, we found AA PrCa derived 2b cells have reduced RNA levels of RYR2, TRPV6 and CALB1 compared to EA PrCa derived LNCaP cells. Reduced transcription can result in lower protein expression and thus activity of calcium regulatory genes. To test this, we stimulated cells with ionomycin and found a rapid increase in intracellular calcium in 2a/2b cells (within 60 seconds) compared to LNCaP/LAPC-4 cells (120-300 seconds). This suggests that decreased transcription correlates to reduced buffering capacity of calcium regulatory genes. Others have shown that increased intracellular calcium reduces AR protein levels. Therefore, we analyzed AR protein expression in a subset of tumors from Cluster A and B. AR levels were lower in adjacent non-tumor and tumor tissue in these overlapping samples. AR low PrCa are associated with basal like features and respond poorly to androgen deprivation therapy. Therefore, we analyzed the PAM50 basal/luminal gene sets and AR target genes and found differentially expression of these genes in AA PrCa derived 2b and EA PrCa derived LNCaP cells. Conclusions: Our study shows that AA men with PrCa have epigenetically dysregulated calcium signaling that is associated with worse DFT. Our ongoing work seeks to identify how these alterations regulate AR expression and thus basal/luminal features. Our long- term goal is to establish novel molecular subtypes using calcium-AR-basal/luminal features that can guide design of rationale therapies in a subset of AA men with PrCa. Citation Format: Swathi Ramakrishnan, Xuan Peng, Eduardo C. Gomez, Kristopher Attwood, Ivan V. Maly, Wilma A. Hoffmann, Wendy Huss, Gissou Azabdaftari, Li Yan, Jianmin Wang, Anna Woloszynska. Intracellular calcium regulates androgen receptor expression and basal-luminal features in prostate cancer from African American men [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-134.

Racial Disparities in Palliative Radiation for African American Men with Metastatic Prostate Cancer

Background: Systemic low-grade inflammation is a candidate risk factor for prostate cancer (PC) in African American (AA) men, potentially contributing to lethal PC development. We previously reported that regular aspirin use is associated with a decreased risk of advanced stage disease and disease recurrence in AA patients with PC. The cancer-preventive benefits of aspirin have been attributed to inhibition of the cyclooxygenase (COX) pathway. Thromboxane A2 (TXA2) is an eicosanoid produced by the COX1 enzyme in platelets. Aspirin can inhibit metastasis by inhibiting COX1 activity and TXA2 synthesis. Hence, we assessed the role of TXA2 in the development of lethal PC. Because TXA2 is unstable, we measured its corresponding primary metabolite, urinary thromboxane B2 (TXB2), to examine the relationship of TXA2 with PC. Method: TXB2 was measured in cases (977) and controls (1022) from the NCI-MD PC Case-Control study using a mass-spectrometry-based assay. TXB2 levels were modeled into low (≤median) and high (&amp;gt;median) levels. We calculated risk factor-adjusted odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression, adjusted hazard ratios (HR) using Cox regression and sub hazard ratios (SHR) using the Fine-Gray model. Results: We observed increased TXB2 levels in cases and an inverse relationship between levels of TXB2 and aspirin use in both cases and controls. For cases who used aspirin, the odds of having high TXB2 were reduced when compared to non-users (OR 0.46 95%CI, 0.34-0.61). This observation remained significant when stratified by race/ethnicity (AA: OR 0.36 95%CI, 0.23-0.54; EA: OR 0.58 95%CI, 0.38-0.88), indicating significant inhibition of TXB2 formation by aspirin, most notably in AA men. Further analysis showed that high TXB2 is associated with a PC case status in AA men (OR 1.44 95%CI, 1.08-1.93) but not EA men (OR 1.07 95%CI, 0.83-1.93), indicating increased TXA2 synthesis in AA men with PC compared to AA men without the disease. Also, men with high TXB2 were more likely to be diagnosed with metastasis compared to men with low TXB2 (OR 4.27 95%CI, 1.48-12.29), indicating more aggressive disease for cases with high TXB2. Furthermore, high TXB2 was associated with all-cause mortality (HR 1.56 95%CI, 1.05-2.33) and PC mortality (HR 4.02 95%CI, 1.46-11.07; SHR 2.89 95%CI, 1.03-8.11) in AA men only. Our findings indicate a distinct association between TXA2 and PC outcomes in AA men. Conclusion: Aspirin use inversely associates with high TXB2. This is of clinical interest as we report that increased TXB2 associates with PC in AA men, with aggressive PC, and with PC death which disproportionally affects AA men. This is consistent with our previous findings that aspirin may reduce lethal PC in AA men and highlights the potential benefit of aspirin for prevention of lethal PC in this high-risk group of men through inhibition of TXA2 synthesis. Citation Format: Maeve Bailey-Whyte, Ginger Milne, Tsion Z. Minas, Tiffany H. Dorsey, Wei Tang, Cheryl J. Smith, Michael B. Cook, Clayton Yates, Stefan Ambs. High urinary thromboxane B2 associates with lethal prostate cancer in African American men and inversely correlates with aspirin use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 34.

INTRODUCTION: African American (AA) men experience greater prostate cancer incidence and mortality compared to European American (EA) men. Growing literature supports associations of neighborhood social factors (NSF) including neighborhood socioeconomic deprivation and residential segregation with advanced or aggressive prostate cancer, and AA men may experience these factors to a greater extent than EA men. Here we tested associations of NSF with prostate tumor RNA expression of stress-related genes, hypothesizing that these factors would be related and contribute to prostate tumor aggressiveness. METHODS: We leveraged available transcriptomic data from prostate tumor tissue for AA and EA men with prostate cancer who received radical prostatectomy surgery at the University of Maryland Medical Center. We geocoded each participant’s address at diagnosis, determined the corresponding census tract, and assigned tract-based Area Deprivation Index (ADI) and Racial Isolation Index (RI) scores to each participant. Based on data availability, ADI analyses included men diagnosed in 2005 or later (118 AA men and 43 EA men), and RI analyses included those diagnosed in 2009 or later (110 AA men and 37 EA men). We evaluated 105 stress-related genes, including those in the Conserved Transcriptional Response to Adversity, among others. We fit separate linear regression models for expression of each gene in relation to ADI or RI, respectively. Models were adjusted for race and age and year at surgery. We obtained q-values (p-values adjusted for multiple comparisons) using the Benjamini-Hochberg method. RESULTS: Median (interquartile range) ADI scores were 116 (101-131) for AA men and 91 (83-103) for EA men, and RI scores were 0.68 (0.38-0.87) for AA men and 0.10 (0.05-0.14) for EA men, indicating greater neighborhood deprivation and Black residential segregation among AA participants. The greatest values for these scores were concentrated in central and west Baltimore. ADI scores were positively and significantly (p&amp;lt;0.05) associated with expression for 11 genes. One gene, HTR6 (serotonin pathway), remained significant after multiple comparison adjustment (beta=0.0029, 95% confidence interval: 0.0014-0.0043; p&amp;lt;0.001; q=0.02). RI scores were positively and significantly associated with expression for 7 genes (p&amp;lt;0.05), but findings did not remain significant after multiple comparison adjustment. Four genes, including HTR6, IFIT2 and MX2 (roles in Type I IFN response), and IGLL1 (antibody synthesis) were significantly associated with both ADI and RI (p&amp;lt;0.05). Top findings among AA men only were similar to the overall results (AA and EA men combined). CONCLUSIONS: We identified several genes in stress-related pathways whose expression in prostate tumor tissue was higher among men with higher neighborhood deprivation or higher racial segregation. Additional analyses will consider other neighborhood measures, including historical redlining, to further investigate the role of NSF in prostate tumor RNA expression, tumor aggressiveness, and prostate cancer disparities. Citation Format: Joseph Boyle, Jessica Yau, Jimmie L. Slade, Derrick Butts, Yuji Zhang, Teklu B. Legesse, Ashley Cellini, Kimberly Clark, Jessica Wimbush, Nicholas Ambulos Jr., Jing Yin, Arif Hussain, Eberechukwu Onukwugha, Cheryl L. Knott, David C. Wheeler, Kathryn Hughes Barry. Neighborhood socioeconomic deprivation, racial segregation, and prostate tumor RNA expression of stress-related genes among African American and European American 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 PR007.

In this study, we compare patterns of differential DNA methylation (DNAm) distinguishing tumor and benign prostate tissue in European American (EA) and African American (AA) men to improve our understanding of biological mechanisms that may underlie prostate cancer (PCa) disparities. In the United States, AA men are more likely to be diagnosed with and to die of PCa compared with EA men. Changes in DNAm accompany tumor development and progression, and differences in DNAm across ancestry groups may be an important lens through which to study PCa disparities. We collected paired tumor and histologically benign formalin-fixed paraffin-embedded tissue blocks from 151 (76 AA, 75 EA) PCa patients undergoing prostatectomy at the University of Chicago. DNA was extracted and genome-wide DNAm was measured at ~850,000 CpG sites using the Illumina MethylationEpic Array. After quality control, 682,694 CpGs remained for analysis. We conducted differential methylation analyses, adjusting for batch, age, and individual and identified 29,236 and 38,035 tumor-associated CpGs in AA and EA respectively (p&amp;lt;5x10-8 and Δβ&amp;gt;0.3) with 25,263 CpGs common to both sets. There was a depletion of differentially methylated CpGs in CpG islands and promoters in both groups, but depletion was stronger in AA. Tumor-associated CpGs within islands and in promoters were more likely to be hypermethylated for both groups, though this was stronger in EA. We identified 2,392 genes with differentially methylated promoters common to both ancestry groups; 223 and 1,045 were unique to AA and EA respectively. Shared gene regions included GSTP1, APC, RARB, and GRASP, which have been previously reported. We assigned CpG sites to genes and used Gene Set Enrichment Analysis to identify differentially methylated pathways. The identified pathways include several previously associated with cancer development including the epithelial mesenchymal transition. We also identified ancestry-specific pathways including the early and late estrogen response pathways in AA. Examining the predictive ability of our differentially methylated CpGs, we found that relatively few CpGs (~10) were sufficient to distinguish tumor and benign tissue in AA and EA men (AUC&amp;gt;0.9). Scores constructed from differentially methylated CpGs in EA were able to predict tumor vs benign in AA (and vice versa) with high accuracy. Finally, we examined the association between ancestry and DNAm in both tumor and benign tissue. Here, 89 and 423 ancestry-associated CpGs were identified in tumor and benign respectively. Overall, we find that differential methylation patterns distinguishing tumor and benign tissue are generally similar for EA and AA men. However, differenced in tumor-associated DNAm as well as the presence of ancestry-associated CpGs provide a rich area for future studies exploring the impact of these differences on cancer development in AA and EA men. Citation Format: Meytal B. Chernoff, Marc Gillard, Kathryn Demanelis, Dayana Delgado, Anthony Williams, Donald Vander Griend, Brandon L. Pierce. Differential DNA methylation in the benign and cancerous prostate tissue of African American and European American men [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 3632.