Prostate Cancer Health Disparities Research Articles

Health Disparities in Prostate Cancer and Approaches to Advance Equitable Care.

The American Cancer Society estimates approximately 268,490 new cases of prostate cancer and approximately 34,500 deaths caused by prostate cancer in the United States for 2022. Globally, a total of 1,414,259 new cases of prostate cancer and 375,304 related deaths were reported in 2020. Well-documented health disparities and inequities exist along the continuum of care for prostate cancer management-from screening to diagnostic and staging work-up, surveillance, and treatment-ultimately impacting clinical outcomes. This session-based article discusses innovative patient-centered approaches to advance equitable prostate cancer care. It begins with a review of domestic health disparities in diagnostic imaging and radiotherapy for prostate cancer, and it summarizes barriers and solutions to achieving health equity, such as equity metrics and practice quality improvement projects. Next, a global perspective is provided that describes approaches to address financial and geographic barriers to prostate cancer care, including specific examples of strategies that emphasize the use of the cheapest method of care delivery while maintaining outcomes for drug delivery and radiotherapy.

Abstract 3619: Vitamin D receptor function in African American prostate cancer is disrupted by reduced BAZ1A/SMARCA5

Abstract The biological drivers of prostate cancer (PCa) health disparities remain enigmatic. There are genomic differences, for example in the incidence of TMPRSS2 and ERG gene fusions which differ between European American (EA) and African American (AA) PCa. Accumulating epidemiological evidence suggests loss of vitamin D receptor VDR signaling contributes to AA PCa. Therefore, we investigated the VDR signaling in AA and EA prostate models. VDR protein levels were comparable between AA (RC43N, RC43T, RC77N, RC77T) and EA cells (HPr1AR, LNCaP) but RIME analyses identified significant AA-EA differences in VDR binding of coactivators (e.g. NCOA5), corepressors (e.g. HDAC2), and components of SWI/SNF and circadian rhythm complexes. ATAC-Seq identified 1α,25(OH)2D3-stimulated gain in nucleosome free (NF) regions was greatest in RC43N (non-malignant AA cells) and enriched for circadian rhythm transcription motifs (e.g. CLOCK). In RC43T AA PCa cells 1α,25(OH)2D3 led to a loss of NF free regions. Similarly, VDR ChIP-Seq revealed the cistrome was greater in AA cell models, and was dynamically altered in RC43N cells by 1α,25(OH)2D3 and overlapped with the SWI/SNF component SMARCA4, but 1α,25(OH)2D3 led to reduced VDR binding in RC43T cells. The 1α,25(OH)2D3-regulated transcriptome was largest in RC43N and RC43T but GSEA terms were frequently and oppositely enriched, for example Reactome S phase genes were negatively enriched in RC43N, but positively enriched in RC43T. Cistrome-transcriptome integration identified the most significant relationships between VDR binding and the magnitude of 1α,25(OH)2D3-regulated genes in RC43N. Global coregulator analyses identified significantly reduced BAZ1A/SMARCA5 in AA PCa in TCGA and a published cohort of ~1500 AA/EA tumors. Restoring BAZ1A expression in cells resulted in significantly enhanced 1α,25(OH)2D3-regulated transcriptome in RC43N and RC43T cells, and hypergeometric tests revealed the significant enrichment of direct VDR target genes. The footprint of altered AA VDR signaling was evident in three previously established clinical cohorts. Serum miRNA that predicted AA progression from HGPIN to PCa were enriched for 1α,25(OH)2D3-regulated VDR targets; AA tumors from a vitaminD3-treated chemotherapy trail were enriched for VDR-bound genes; and, tumors from men with low serum 25(OH)D3 levels were significantly enriched for VDR target genes identified in AA but not EA PCa. Together, these data suggest VDR transcriptional control is most potent and dynamic in AA prostate cells, and is primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmental-regulated serum vitamin D3 levels most acutely suppress these actions in AA PCa. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes that contributes to PCa health disparities. Citation Format: Shahid Hussain, Manjunath Siddappa, Sajad A. Wani, Hedieh Jafari, Jaimie S. Gray, Hsu-Chang Wu, Hancong Tang, Mark D. Long, Isra Elhussin, Balasubramanyam Karanam, Honghe Wang, Rebecca Morgan, Gary Hardiman, Isaacson B. Adelani, Rotimi Oladapo, Adam R. Murphy, James R. Marshall, Chanita Highes Halbert, Lara E. Sucheston-Campbell, Clayton Yates, Moray J. Campbell. Vitamin D receptor function in African American prostate cancer is disrupted by reduced BAZ1A/SMARCA5 [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 3619.

Abstract 3687: Implementing geospatial technology to understand the prostate cancer health burdens and socioeconomic status in Alabama

Abstract Socioeconomic status and health disparities are a significant liability for the prevalence of many diseases, including cancer. Among many contributing factors, lack of socioeconomic advancement and inequality in resource distribution is closely associated with prostate cancer occurrence. The State of Alabama has one of the highest rates of prostate cancer in the nation and the third cancer epidemic at the state level. Due to widespread disparities in infrastructure development, political willpower, equal healthcare, and education opportunity, Alabama's Black Belt region has been further divided by socioeconomic statuses among the majority (Whites) and minority (African American) populations. The purpose of this research is to recognize Alabama's health burdens and socioeconomic status using geo-spatial technology (GIS) to examine prostate cancer health disparity. GIS has become a valuable decision-making tool in understanding the public health care sectors, including prostate cancer prevalence. GIS supports assembling spatial and non-spatial data, displays the spatial distribution of health disparities, and underlines further interconnectivity of policy-related questions. This research incorporates county-level prostate cancer data using GIS and outlining the correlation between prostate cancer prevalence and socioeconomic factors to understand Alabama's cancer health disparity and equity. A combination of socioeconomic factors and state and federal-level cancer epidemic data sources underline Alabama's black belt region (predominantly African American) prostate cancer prevalence is higher than the non-black belt. The GIS analysis demonstrated that effective cancer prevention programs are needed to eliminate health disparities and enhance health equity among underserved populations of Alabama. Citation Format: Ram Alagan, Seela Aladuwaka, Rajesh Singh, Upender Manne, Manoj K. Mishra. Implementing geospatial technology to understand the prostate cancer health burdens and socioeconomic status in Alabama [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 3687.

Racial disparities in prostate cancer: A complex interplay between socioeconomic inequities and genomics

The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the important role of biology. Significant differences have been observed in prostate cancer biology between ancestral groups that may contribute to prostate cancer health disparities. Notably, relative to White men, Black men with prostate cancer exhibit increased androgen receptor signaling, genomic instability, metabolic dysregulation, and inflammatory and cytokine signaling. Immediate actions are needed to increase multi-center, interdisciplinary research to bridge the gap between social and biological determinants of prostate cancer health disparities.

Physician Attitudes and Self-reported Practices Toward Prostate Cancer Screening in Black and White Men.

Updated 2018 prostate cancer screening guidelines recommend informed decision-making discussions, which should include education on prostate cancer's disproportionate impact on Black men. It is unknown whether academic family physicians follow these guidelines. Family physicians were surveyed as part of the 2020 Council of Academic Family Medicine Educational Research Alliance (CERA) survey. We used χ2 to compare physicians' knowledge and screening practices stratified by physician age, gender, and percentage of Black patients in patient panel. We calculated logistic regressions predicting shared decision-making conversations, barriers to shared decision-making, inclusion of race in prostate cancer screening approach, and prostate-specific antigen (PSA) testing adjusted for physician age, gender, and percentage of Black patients. Physicians reported engaging in shared decision-making for prostate cancer screening in half of eligible men. Only 29.2% of physicians reported routinely informing Black men of their increased prostate cancer risk. In logistic regressions, physician gender (female) and fewer Black patients in panel (<25%) were associated with lower frequency of shared decision-making with Black patients. Physician age (<40 years) was associated with not discussing race during screening discussions (OR 2.24, 95% CI 1.55-3.23). Most academic family physicians do not appropriately inform Black men of increased prostate cancer risk, with younger physicians less likely to discuss race than older physicians. Female physicians, and physicians who see fewer Black patients, are less likely to have shared decision-making conversations with Black patients. This suggests educational efforts for these groups are needed to address health disparities in prostate cancer.

Abstract PR-17: The role of HMGA2 and CLK3 in prostate cancer health disparities

Abstract African American men (AA) suffer disproportionately from prostate cancer (PCa) displaying higher incidence and mortality rates when compared to Caucasian-American men (CA). Recent studies have shown that high mobility group A2 (HMGA2), a non-histone chromatin binding protein, plays a critical role in promoting metastasis. HMGA2 full-length/wild-type and truncated (lacking the 3'UTR) isoforms are overexpressed in several cancers, however, their distinct roles in PCa have not been reported. Literature has previously revealed a splicing factor, CDC-like kinase 3 (CLK3), that promotes splicing of wild-type HMGA2 to create the truncated HMGA2 isoform. We hypothesize that HMGA2 isoforms may play differential roles to promote PCa progression according to ethnicity. qPCR analysis of patient tissue of varying PCa stages was conducted to look at the mRNA expression of HMGA2 isoforms and CLK3. RNA-Seq was performed on LNCaP prostate cancer cell lines stably overexpressing wild-type or truncated HMGA2 and compared to Neo control. Both wild-type and truncated HMGA2 increased with increased PCa gleason grade. AA when compared to CA, displayed higher levels of truncated HMGA2 and its splicing factor, CLK3. RNA-Seq analysis revealed distinct gene sets regulated by truncated HMGA2 compared to wild-type HMGA2, including upregulation of a distinct set of genes involved in androgen signaling. These results indicate that HMGA2 isoforms are disproportionately expressed in AA and CA and increase with PCa progression. The regulation of differential genes by HMGA2 isoforms suggest that they may use distinct pathways to promote PCa. Citation Format: Taaliah Campbell, Ohuod Hawsawi, Valerie Odero-Marah. The role of HMGA2 and CLK3 in prostate cancer health disparities [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 PR-17.

Abstract 778: CD24 mutant p53 contribute to racial disparities in prostate cancer

Abstract African-American (AA) men have the highest rate of prostate cancer among racial or ethnic groups. CD24, a cell-surface protein anchored by glycosyl-phosphatidyl-inositol (GPI), often is over-expressed in cancers and serves as a marker for poor prognosis of human cancer, including prostate cancer. Using a functional analysis of prostate cancer cells, we found a CD24-dependent inactivation of mutant p53, but the clinical significance of this observation remained uncertain. Here, we validated these results with samples of human prostate cancer and explored the role of a CD24-p53 axis in racial disparities of prostate cancer. Our bioinformatics analysis of public datasets, including TCGA data, confirmed higher levels of CD24 mRNA expression in late-stage and metastatic prostate cancer. In the present study, we addressed the association of CD24 with mutant p53 and their differential expression between AA and European-American (EA) prostate cancers and assessed whether cells with CD24 and mutant p53 contribute to health disparities in prostate cancer. CD24, mutant p53, MDM2, and ARF proteins were expressed in 55%, 24%, 39%, and 68% of prostate cancer samples, respectively. CD24 and mutant p53 were present more frequently in late-stage and metastatic prostate cancer. The presence of CD24 was associated with a > 4-fold risk of metastasis, which included lymph node and distant metastases. H-score analysis showed positive correlations of CD24 expression with mutant p53 and MDM2. A racial disparity was evident for CD24 but not for mutant p53. In 32 CD24+/mutant p53+ cases, a TP53R273H mutation was found in five cases, but no TP53R175H mutation was found. The CD24-p53 axis may contribute to aggressive and metastatic prostate cancers, especially those of AAs. Citation Format: Xuelian Cui, Shuaibin Wang, Lizhong Wang. CD24 mutant p53 contribute to racial disparities in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 778.

Immune Inflammation Pathways as Therapeutic Targets to Reduce Lethal Prostate Cancer in African American Men.

Simple SummaryMen of African descent are twice as likely to die of prostate cancer than other men. While equal access to care is the key target to improve cancer survival, it is now known that there are differences in disease biology and risk factor exposure across population groups. These differences could be causatively linked to the existing prostate cancer health disparities. In this review, we will discuss the candidate role of inflammation and the immune response as contributing factors to the excessive burden of lethal prostate cancer among men of African ancestry. Furthermore, we will introduce the concept that these immunogenic vulnerabilities could be exploited to address the adverse outcomes experienced by these men. Lastly, we will summarize how these immunogenic and inflammatory differences could be targeted using current treatments to improve survival for men of African descent.Despite substantial improvements in cancer survival, not all population groups have benefitted equally from this progress. For prostate cancer, men of African descent in the United States and England continue to have about double the rate of fatal disease compared to other men. Studies suggest that when there is equal access to care, survival disparities are greatly diminished. However, notable differences exist in prostate tumor biology across population groups. Ancestral factors and disparate exposures can lead to altered tumor biology, resulting in a distinct disease etiology by population group. While equal care remains the key target to improve survival, additional efforts should be made to gain comprehensive knowledge of the tumor biology in prostate cancer patients of African descent. Such an approach may identify novel intervention strategies in the era of precision medicine. A growing body of evidence shows that inflammation and the immune response may play a distinct role in prostate cancer disparities. Low-grade chronic inflammation and an inflammatory tumor microenvironment are more prevalent in African American patients and have been associated with adverse outcomes. Thus, differences in activation of immune–inflammatory pathways between African American and European American men with prostate cancer may exist. These differences may influence the response to immune therapy which is consistent with recent observations. This review will discuss mechanisms by which inflammation may contribute to the disparate outcomes experienced by African American men with prostate cancer and how these immunogenic and inflammatory vulnerabilities could be exploited to improve their survival.

Abstract PR05: Epigenetic disruption of vitamin D receptor signaling in African American prostate cancer alters circadian signaling networks

Abstract The current study aimed to define the genomic functions of the vitamin D receptor (VDR) in African American (AA) prostate cancer (PCa) compared to European American (EA) counterparts. VDR-dependent ChIP-Seq and RNA-Seq gene was undertaken in EA (non-malignant HPr1AR and malignant LNCaP) and AA (non-malignant RC43N and malignant RC43T) prostate models, combined with analyses of three PCa cohorts. In AA prostate models the VDR is highly expressed, binds more frequently, and is enriched in active and poised enhancers. Motif analyses revealed selective enrichment, including ZBTB33/KAISO in AA cells and ERG family members in EA cells and, similarly, GIGGLE analyses revealed AA VDR cistromes were significantly overlapped with core circadian rhythm transcription factors (e.g. NONO). Combining VDR-dependent ChIP-Seq and RNA-Seq established that AA cells displayed a significantly stronger transcriptional response, compared to EA cells, and was most responsive in non-malignant RC43N. For example, RC43N transcriptional responses were enriched for circadian rhythm (NES 2.7) and inflammation, whereas in RC43T the same gene networks were repressed. To reveal how VDR/1,25(OH)2D3 signaling is corrupted in AA PCa, we mined TCGA data and revealed that the BAZ1A/SMARCA5 chromatin remodeling complex was uniquely altered in TMPRSS2:ERG fusion negative AA PCa. We are currently examining the impact of BAZ1A on the 1,25(OH)2D3 responsiveness. We also identified miRNA associated with progression from HGPIN to PCa in AA men, and that ~30% were bound by VDR and regulated by 1,25(OH)2D3, although ~5% of EA progression miRNA were VDR-responsive. For example, VDR binds to miR-199b, is uniquely 1,25(OH)2D3 up-regulated in RC43N but repressed in RC43T, and associates with AA progression from HGPIN to PCa. MiR-199b regulates expression of NPAS2, a core circadian transcription factor. Finally, leveraging a previously analyzed cohort of 1,25(OH)2D3-treated PCa patients revealed that AA tumors were intrinsically more 1,25(OH)2D3-responsive than EA counterparts, reflecting the cell line analyses. 1,25(OH)2D3 regulated circadian transcriptional regulators (e.g. NOCT and MYBBP1A) and inflammatory signals. Together, these data suggest VDR transcriptional control in AA men is more dynamic than in EA men, and is primed to govern inflammatory and circadian rhythm pathways. This is frequently disrupted, including by altered BAZ1A/SMARCA5 expression and/or reduced environmental-regulated serum vitamin D3 levels, and leads to altered regulation of circadian rhythm process, and inflammatory signals. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes that contributes to PCa health disparities. Citation Format: Manjunath Siddappa, Sajad D. Wani, Jaimie S. Gray, Mark D. Long, Hedieh Jafari, Hsuchang Wu, Honhe Wang, Rebecca Morgan, Gary Hardiman, James Marshall, Chanita Hughes-Halbert, Lara E. Sucheston-Campbell, Clayton L. Yates, Moray J. Campbell. Epigenetic disruption of vitamin D receptor signaling in African American prostate cancer alters circadian signaling networks [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 PR05.

Abstract 3511: Racial differences in circulating mitochondria-derived peptides may contribute to prostate cancer health disparities

Abstract INTRODUCTION AND OBJECTIVES: Our group identified multiple small open reading frames (ORFs) in the mitochondrial genome. These ORFs produce small mitochondrial-derived peptides (MDPs) that are measurable in plasma including humanin, small humanin-like peptide-2 (SHLP2), and mitochondrial open reading frame of the 12S rRNA (MOTSc). Previously we found that higher serum SHLP2 was linked with lower prostate cancer (PC) risk in white men, but no significant association was observed in black men. We tested whether SHLP2 and other MDPs as measured in plasma correlated with PC risk by race in a separate sample of men undergoing prostate biopsy. METHODS: Plasma SHLP2, humanin, and MOTSc were measured by ELISA in 198 men (50/49 white/black cases; 50/49 white/black controls) undergoing prostate biopsy at the Durham Veterans Affair hospital. Logistic and multinomial regression models were used to test the association between each MDP and PC diagnosis and low-grade (grade group 1) and high-grade PC (grade group 2-5). Models were adjusted for age, body mass index, digital rectal examination, and PSA. We tested the interaction between MDPs and race in predicting PC. RESULTS: There was a statistically significant p-interaction between all 3 MDPs and race for predicting PC (all p-interactions values lower than 0.01). Among white men, higher values of all MDPs were significantly associated with lower PC diagnosis (all p-values lower than 0.001). In contrast, in black men, all MDPs were unrelated to PC diagnosis. Similarly, higher expression of all MDPs was associated with decreased risk of both low- and high-grade PC in white men (all p-values lower than 0.005) but none were associated with low- or high-grade in black men. Black controls had lower MOTSc (p-value equal 0.026) and SHLP2 (p-value equal 0.001) values than white controls. CONCLUSIONS: Higher expression of all three MDPs studied (plasma SHLP2, humanin, and MOTSc) were associated with lower PC risk in white men but not in black men. However, in general, black controls had lower MDP levels than white controls. These data support the importance of MDPs and perhaps mitochondrial dysfunction in PC and suggest greater dysfunction in black men (lower MDP levels in controls), which may contribute to excess PC risk in black men, though this requires confirmation in future larger studies. Funding: Supported in part by DODW81XWH, K24CA160653, and U54CA233465. Citation Format: Adela Ramirez-Torres, Allison L. Reagan, Lauren E. Howard, Emily Wiggins, Adriana C. Vidal, Junxiang Wang, Stephen J. Freedland, Pinchas Cohen. Racial differences in circulating mitochondria-derived peptides may contribute to prostate cancer health disparities [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3511.

Abstract B084: Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes

Abstract Background: We previously showed that Nrdp1, an E3 ubiquitin ligase, is transcriptionally regulated by the androgen receptor (AR) in prostate cancer (CaP) cells and that Nrdp1 can post-translationally regulate ErbB3 (an EGFR family member) levels via ubiquitination and subsequent proteasomal degradation. Increased levels of ErbB3 are associated with worse CaP patient outcome. The goal of the current study was to determine whether dysregulation of the AR-Nrdp1-ErbB3 axis contributes to prostate cancer health disparities for African American (AA) men, and to identify the underlying mechanisms involved. Methods: Expression levels and localization of AR, Nrdp1, and ErbB3 were assessed in a total of 208 CaP patient samples (50 African American (AA) and 158 Caucasian (CA) CaP patients) and two cell lines (LNCaP (CA) and MDAPCa2b (AA)). Expression levels and localization of these molecules were determined by immunohistochemistry (IHC) and subcellular fractionation and western blot. A combination of knockdown (siRNA), forced overexpression (Nrdp1-FLAG construct), and treatment with enzalutamide or synthetic androgen (R1881) experiments were employed to investigate the relationship between AR, Nrdp1, and ErbB3 expression levels and localization and to identify differences in AA and CA cell lines. Immunoprecipitation allowed for investigation of the mechanisms which facilitate nuclear transport of Nrdp1. Results: A statistically significant negative association between cytoplasmic levels of AR (AR C) and nuclear Nrdp1 (Nrdp1 N) exists in both Caucasian (CA) and African American (AA) prostate cancer (CaP) patients, but this association was stronger in AA patients compared to CA patients (Spearman correlation coefficient of -0.62 for AA patients, and -0.36 for CA patients). Increased nuclear Nrdp1 expression levels were associated with increased 5-year survival rates, and reduced nuclear Nrdp1 expression levels predicted biochemical recurrence (AUC 0.63). Dysregulation of the AR-Nrdp1-ErbB3 axis in AA CaP cells was also observed in cell line studies; AA CaP cells expressed significantly lower levels of both total and nuclear Nrdp1 compared to their CA CaP counterparts. Manipulation of AR expression levels and localization via knockdown and inhibition with enzalutamide had a lesser impact on Nrdp1 expression levels and localization in AA versus CA CaP cells. Immunoprecipitation studies demonstrated that Nrdp1 can bind to AR in CA CaP cells but not AA CaP cells. Conclusions: Our combined data indicate that dysregulation of the AR-Nrdp1-ErbB3 axis occurs to a larger extent in AA than CA CaP cells and that this can contribute to worse patient outcomes. Our data also indicate that lack of binding between AR and Nrdp1 in AA CaP cells may account for the lower levels of nuclear Nrdp1 observed in AA CaP cells. Further understanding of the mechanisms which regulate Nrdp1 levels and localization may allow for the development of treatments which help abrogate cancer health disparities. Note: This abstract was not presented at the conference. Citation Format: Anhao Sam, Elizabeth Browning, Shawna Evans, Thomas Steele, Paramita Ghosh, Ruth Vinall. Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes [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 B084.

Abstract PR06: Research on prostate cancer in men of African ancestry: Defining the roles of genetics, tumor markers, and social stress

Abstract African American men have a >60% higher incidence and are more likely to be diagnosed with aggressive prostate cancer than white men. The reasons are not clear but are likely to include a multitude of factors such as social factors (e.g., lifetime stress), inherited susceptibility, and tumor-related features such as somatic alterations and local inflammation in the microenvironment. To investigate these hypotheses, over the next five years, we will establish a large, national, population-based cohort study, RESPOND (Research on Prostate Cancer in Men of African Ancestry: Defining the Roles of Genetics, Tumor Markers and Social Stress) of 10,000 African American men with incident prostate cancer identified through nine U.S. cancer registries from states that include 38% of all African American prostate cancer cases in the U.S. We will also recruit men who wish to volunteer through our website (RespondStudy.org). The cohort will provide comprehensive information on 1) multilevel stressors over the lifecourse; 2) geographic data on residential segregation, and social and built environmental factors; 3) lifestyle factors and health behaviors; 4) disease-specific factors including PSA screening history and treatment choice; 5) germline DNA to study genetic susceptibility; and 6) tumor samples to study somatic changes associated with aggressive disease. No previous study has attempted to obtain information across these domains in a single large cohort in order to understand the independent and joint contributions of these factors. Leveraging the RESPOND resource and investigator expertise, we have designed a research program composed of four Projects that are supported by four Cores, which are all focused on the central theme of identifying social and biologic factors related to prostate cancer disease aggressiveness in African American men. These Projects include the investigation of multilevel social stressors across the lifecourse in relationship with aggressive prostate cancer (Project 1); genome-wide discovery efforts of germline susceptibility loci for aggressive prostate cancer and examination of the relationship between germline and somatic variation (Project 2); the identification of underlying somatic alterations in prostate cancer tumors and biologic pathways that are related to aggressive disease (Project 3); and a detailed assessment of inflammation in the tumor microenvironment as it relates to prostate cancer aggressiveness (Project 4). Each of the four Projects addresses a distinct research domain, but together they will provide a comprehensive picture of the major factors that contribute to aggressive prostate cancer in African American men. The information we will discover is likely to help in explaining prostate cancer health disparities and have immediate clinical implications in the areas of improved patient stratification and personalized medicine for African American men. This abstract is also being presented as Poster C058. Citation Format: Ann S. Hamilton, Scarlett Gomez, Xiao-Cheng Wu, Kevin Ward, Melissa Bondy, Rosemary Cress, Jennifer Beebe-Dimmer, Karen Pawlish, Jong Park, Iona Cheng, Antoinette Stroup, Thomas Sellers, Susan Gundell, Angelo Demarzo, Denise Modjeski, Stephen Chanock, Salma Shariff-Marco, Mindy DeRouen, John Carpten, Franklin Huang, Karen Sfanos, Tamara Lotan, David Conti, Christopher Haiman. Research on prostate cancer in men of African ancestry: Defining the roles of genetics, tumor markers, and social stress [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 PR06.

Abstract B083: Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes

Abstract Background: We previously showed that Nrdp1, an E3 ubiquitin ligase, is transcriptionally regulated by the androgen receptor (AR) in prostate cancer (CaP) cells and that Nrdp1 can post-translationally regulate ErbB3 (an EGFR family member) levels via ubiquitination and subsequent proteasomal degradation. Increased levels of ErbB3 are associated with worse CaP patient outcome. The goal of the current study was to determine whether dysregulation of the AR-Nrdp1-ErbB3 axis contributes to prostate cancer health disparities for African American (AA) men, and to identify the underlying mechanisms involved. Methods: Expression levels and localization of AR, Nrdp1, and ErbB3 were assessed in a total of 208 CaP patient samples (50 African American (AA) and 158 Caucasian (CA) CaP patients) and two cell lines (LNCaP (CA) and MDAPCa2b (AA)). Expression levels and localization of these molecules were determined by immunohistochemistry (IHC) and subcellular fractionation and western blot. A combination of knockdown (siRNA), forced overexpression (Nrdp1-FLAG construct), and treatment with enzalutamide or synthetic androgen (R1881) experiments were employed to investigate the relationship between AR, Nrdp1, and ErbB3 expression levels and localization and to identify differences in AA and CA cell lines. Immunoprecipitation allowed for investigation of the mechanisms which facilitate nuclear transport of Nrdp1. Results: A statistically significant negative association between cytoplasmic levels of AR (AR C) and nuclear Nrdp1 (Nrdp1 N) exists in both Caucasian (CA) and African American (AA) prostate cancer (CaP) patients, but this association was stronger in AA patients compared to CA patients (Spearman correlation coefficient of -0.62 for AA patients, and -0.36 for CA patients). Increased nuclear Nrdp1 expression levels were associated with increased 5-year survival rates, and reduced nuclear Nrdp1 expression levels predicted biochemical recurrence (AUC 0.63). Dysregulation of the AR-Nrdp1-ErbB3 axis in AA CaP cells was also observed in cell line studies; AA CaP cells expressed significantly lower levels of both total and nuclear Nrdp1 compared to their CA CaP counterparts. Manipulation of AR expression levels and localization via knockdown and inhibition with enzalutamide had a lesser impact on Nrdp1 expression levels and localization in AA versus CA CaP cells. Immunoprecipitation studies demonstrated that Nrdp1 can bind to AR in CA CaP cells but not AA CaP cells. Conclusions: Our combined data indicate that dysregulation of the AR-Nrdp1-ErbB3 axis occurs to a larger extent in AA than CA CaP cells and that this can contribute to worse patient outcomes. Our data also indicate that lack of binding between AR and Nrdp1 in AA CaP cells may account for the lower levels of nuclear Nrdp1 observed in AA CaP cells. Further understanding of the mechanisms which regulate Nrdp1 levels and localization may allow for the development of treatments which help abrogate cancer health disparities. Citation Format: Anhao Sam, Shawna Evans, Elizabeth Browning, Sheryl Krig, Neelu Batra, Thomas Steele, Salma Siddqui, Paramita Ghosh, Ruth Vinall. Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes [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 B083.

Abstract C028: Hypoxia-associated genes on disparities in the aggressiveness of prostate cancer

Abstract The incidence of prostate cancer (PCa) is 70% greater and the mortality rate 137% higher in African-American men (AAM) relative to Caucasian-American men (CAM) (Siegel et al., 2016). AAM also show faster tumor growth, higher levels of PSA, and more aggressive disease relative to CAM (Martin et al., 2013). These data, related to the biology of PCa, suggest that biologic mechanisms contribute to PCa health disparities. Because stratification by clinical parameters alone is not sufficient to predict aggressive PCa, there is an unmet need of reliable biomarkers to anticipate outcome and disease progression. This study was designed to identify hypoxia-associated genes with the potential to anticipate the risk of aggressive PCa in a race-specific manner. Seventy annotated cases with documented follow-up for evidence of biochemical recurrence (BCR) were located. Of these, 22 were AAM (8 with BCR and 14 without BCR) and 48 were CAM (31 with BCR and 17 without BCR). Next, we performed a global sequencing analysis in RNA extracted from formalin-fixed, paraffin-embedded blocks. Among 27 hypoxia-associated genes associated with race and PCa by use of Cox proportional hazards regression analysis (p ≤ 0.05), we identified three genes related with BCR and race: regulator of G-protein signaling 1 (RGS1), nuclear receptor subfamily 3, group C, member 1-glucocorticoid receptor (NR3C1), and myosin light chain kinase (MYLK). A race-independent in silico analysis utilizing TCGA data suggested tumor-specific association between transcripts of RGS1, NR3C1, and MYLK and Gleason score. Likewise, low expression of these transcripts was suggestive of poor survival. Currently, we are analyzing transcripts of these three hypoxia-associated genes by independent techniques. Integration of gene expression data with clinical parameters of prognosis will allow us to develop predictive scores. These studies may enable race-specific differentiation of patients at higher and lower risk of BCR. Our findings underscore the prognostic value of hypoxia-regulated genes in aggressive PCa. They also warrant studies to establish the relevance of RGS1, NR3C1, and MYLK as race-specific markers. Funding sources: GMaP 2 Pilot Grant (IE). Citation Format: Ingrid C. Espinoza, Carlos S. Moreno, Christian R. Gomez. Hypoxia-associated genes on disparities in the aggressiveness of prostate cancer [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 C028.

Somatic mutations in the DNA repairome in prostate cancers in African Americans and Caucasians

Most hereditary tumors show aberrations in DNA repair genes or their regulators. In contrast, only a minority of sporadic tumors show alterations in these genes. As a result, genomic instability is currently considered an enhancer of tumorigenesis rather than an obligatory event in this process. However, tumor heterogeneity presents a significant technical challenge for most cancer genomics studies performed at less than 100× mean resolution depth. To address the importance of genomic instability in prostate carcinogenesis and tumor progression, we performed ultrahigh depth exome sequencing of 124 DNA damage repair/response (repairome) genes in 63 tumors and matched normal tissue samples in African Americans and Caucasians. The average sequence depth was 712-fold for DNA isolated from normal tissue and 368-fold for FFPE tumors. We identified 671 somatic mutations in tumors from African Americans and 762 somatic mutations in tumors in Caucasians. The most frequently mutated DNA repairome genes were EXO1, ATR, POLQ, NEIL3, ERCC6, BRCA2, BRCA1, XPC, JAG1, RPA1, POLE, ATM, and LIG1 in African American men, and POLQ, NEIL3, POLB, BRCA2, EXO1, ERCC6, ATR, RBBP8, BRCA1, ATM, JAG1, XPC, and POLE in Caucasians. We found that 89% of tumors had at least one mutation in nucleotide excision repair pathway genes in African Americans, whereas >40% of tumors had mutations in base excision repair pathway genes in Caucasians. We further identified a marginal increase in mutation rate in tumors in African Americans with increasing age. Tumors in Caucasians did not show a correlation with age, but a progressive increase in the mutation rate was observed at higher Gleason scores. Our data reveal significant differences in the molecular signatures in the DNA repairome in prostate cancer between African Americans and Caucasians. These data also have substantial implications regarding the well-known health disparities in prostate cancer, such as the higher mortality in African Americans than Caucasians.

Use of empiric methods to inform prostate cancer health disparities: Comparison of neighborhood-wide association study "hits" in black and white men.

Black men are more likely to die of prostate cancer (PCa) compared with white men. Factors ranging from genetics to neighborhood environment contribute to these disparities. However, unlike genetics, agnostic investigations that identify candidate variables from large-scale data, and that allow for empiric investigations into differential associations between neighborhood and PCa by race/ethnicity, to the authors' knowledge have not been well explored. Thus, herein, the authors built on their previously developed, empiric neighborhood-wide association study (NWAS) in white men and conducted a NWAS in black men to determine whether findings differed by race. Pennsylvania Cancer Registry data were linked to US Census data. For the NWAS in non-Hispanic black men, the authors evaluated the association between 14,663 neighborhood census variables and advanced PCa (11 high-stage and/or high-grade cases and 8632 low-stage and/or low-grade cases), adjusting for age, diagnosis year, spatial correlation, and multiple testing. Odds ratios and 95% credible intervals were reported. Replication of NWAS findings across black and white races was assessed using Bayesian mixed effects models. Five variables related to housing (3 variables), education (1 variable), and employment and/or transportation (1 variable) were found to be significantly associated with advanced PCa in black men compared with 17 socioeconomic variables (mostly related to poverty and/or income) in white men. The top hit in black men was related to crowding in renter-occupied housing (odds ratio, 1.10; 95% credible interval, 1.001-1.12). Nine of 22 NWAS hits (4 of 5 hits in black men) were replicated across racial/ethnic groups. Different neighborhood variables, or "candidates," were identified across race-specific NWASs. These findings and empiric approaches warrant additional study and may inform PCa racial disparities, particularly future gene-environment studies aimed at identifying patients and/or communities at risk of advanced PCa.

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance.

Alternative splicing (AS) has been shown to participate in prostate cancer development and progression; however, a link between AS and prostate cancer health disparities has been largely unexplored. Here we report on the cloning of a novel splice variant of FGFR3 that is preferentially expressed in African American (AA) prostate cancer. This novel variant (FGFR3-S) omits exon 14, comprising 123 nucleotides that encode the activation loop in the intracellular split kinase domain. Ectopic overexpression of FGFR3-S in European American (EA) prostate cancer cell lines (PC-3 and LNCaP) led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared with FGFR3-L (retains exon 14). The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and antiapoptotic activities, as well as a modest but significant gain in cell motility. Moreover, the FGFR3-S-conferred proliferative and motility gains were highly resistant to the pan-FGFR small-molecule inhibitor dovitinib and the antiapoptotic gain was insensitive to the cytotoxic drug docetaxel, which stands in marked contrast with dovitinib- and docetaxel-sensitive FGFR3-L. In an in vivo xenograft model, mice injected with PC-3 cells overexpressing FGFR3-S exhibited significantly increased tumor growth and resistance to dovitinib treatment compared with cells overexpressing FGFR3-L. In agreement with our in vitro and in vivo findings, a high FGFR3-S/FGFR3-L expression ratio in prostate cancer specimens was associated with poor patient prognosis. IMPLICATIONS: This work identifies a novel FGFR3 splice variant and supports the hypothesis that differential AS participates in prostate cancer health disparities.

Upregulation of miR-130b Contributes to Risk of Poor Prognosis and Racial Disparity in African-American Prostate Cancer.

Prostate cancer incidence and mortality rates are higher in African-American (AA) than in European-American (EA) men. The main objective of this study was to elucidate the role of miR-130b as a contributor to prostate cancer health disparity in AA patients. We also determined whether miR-130b is a prognostic biomarker and a new therapeutic candidate for AA prostate cancer. A comprehensive approach of using cell lines, tissue samples, and the TCGA database was employed. We performed a series of functional assays such as cell proliferation, migration, invasion, RT2-PCR array, qRT-PCR, cell cycle, luciferase reporter, immunoblot, and IHC. Various statistical approaches such as Kaplan-Meier, uni-, and multivariate analyses were utilized to determine the clinical significance of miR-130b. Our results showed that elevated levels of miR-130b correlated with race disparity and PSA levels/failure and acted as an independent prognostic biomarker for AA patients. Two tumor suppressor genes, CDKN1B and FHIT, were validated as direct functional targets of miR-130b. We also found race-specific cell-cycle pathway activation in AA patients with prostate cancer. Functionally, miR-130b inhibition reduced cell proliferation, colony formation, migration/invasion, and induced cell-cycle arrest. Inhibition of miR-130b modulated critical prostate cancer-related biological pathways in AA compared with EA prostate cancer patients. In conclusion, attenuation of miR-130b expression has tumor suppressor effects in AA prostate cancer. miR-130b is a significant contributor to prostate cancer racial disparity as its overexpression is a risk factor for poor prognosis in AA patients with prostate cancer. Thus, regulation of miR-130b may provide a novel therapeutic approach for the management of prostate cancer in AA patients.

Abstract 5133: Identification of distinct gene expression profiles in African Americans and Caucasian men with prostate cancer

Abstract Introduction African Americans (AA) are disproportionately affected by prostate cancer (PCa) compared to European Americans (EA). Genetic and epigenetic differences have been implicated in this racial disparity. Present PCa diagnostic and treatment regimens have focused mainly on gene fusion product involving the androgen driven transmembrane protease serine 2 (TMPRSS2) and the transcription factor, ETS related gene (ERG). However, TMPRSS2:ERG (T2E) fusion product is common mainly to EA (50-80% of patients) and has lower prevalence amongst other ethnicities including AAs (10-30%), Japanese and Chinese patients. In addition, T2E negative PCa subtype has been associated with increased risk of developing castration resistant PCa (CRPC). This study aims at classifying PCa by molecular and pathologic subtypes that drive disease aggressiveness in patients of AA and EA ancestry. Methodology Prostate cancer tissue slides obtained from EA and AA patients were stained for ERG expression. Laser-capture micro-dissected RNAs from formalin-fixed paraffin-embedded tissues were used for RNA-seq. DESeq2 was used as a statistical procedure to call differentially expressed genes (DEGs) in different samples. Data set from Powell was also analyzed for DEGs between ERG positive and ERG negative samples. Leading-Edge Analysis (GSEA v2.2.4) was performed to determine the representation of DEGs across enriched gene sets. Results 32.4% of EA were ERG positive compared to 29% of AA that stained positive. More EA samples (26.4%) had high intensity staining (2≥ on a 1 - 3 scale) compared to AA samples (25.8%). Over 11% of EA samples had high (4) distribution of ERG positive staining compared 6.5% in AA samples. Analysis of the Powell dataset (GSE41696) revealed 301 DEGs and gene set enrichment analysis identified immune system process, regulation of cellular component and homeostatic process as most biological processes affected by DEGs. Other processes significantly affected included: cell motility, cell activation and regulation of locomotion. At least 15 genes including: CCL5, TLR4, PIK3CB, CD86, KIT, CD40, ITGB3, PDGFRA, LEF1, HIF1A, CLU, PLA2G6, GLI3, PIK3CA and TNNB1, were present in at least 10 enriched gene sets. The DEGs across enriched gene sets showed gene signatures involved in Wnt signaling, PI3K, chemokines and receptor tyrosine kinases. Conclusion Specific sets of genes are differentially enriched between EGR-/AR- and ERG+/AR+. These findings suggest that PCas have a distinct gene expression profile in the absence of the T2E fusion, which may act as a driver of disease aggressiveness and racial health disparities in PCa. Identifying these differences in gene-signature expression and signaling transduction pathways will allow stratification of men across races and identify, early on, those individuals who are likely to develop the most aggressive disease. Citation Format: Joakin Mori, Raven Williams, Hui-Xian Lin, Alahni Becks, Jason White, Balasubramanyam Karanam, Clayton Yates, Honghe Wang. Identification of distinct gene expression profiles in African Americans and Caucasian men with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5133.

Abstract 2637: Novel targeted therapy-resistant FGFR3 splice variant increases oncogenic phenotype in African American prostate cancer

Abstract Introduction: In this study, we investigate the role of alternative splicing in the receptor tyrosine kinase family on prostate cancer health disparities in African American men. Background: Prostate cancer (PCa) is the most diagnosed cancer in men and the second leading cause of male-cancer related deaths in the U.S. Dramatic ethnic disparities have been observed in PCa patients, as African American (AA) men are 60% more likely to be diagnosed with PCa and have a 2.4 fold higher mortality rate compared to European American (EA) men. Increasing evidence suggests that, after accounting for epidemiological factors, a remaining component of this disparity is due to intrinsic genetic and biological factors. Interestingly, exon array data from our lab suggest that differential alternative splicing (dAS) may be occurring in AA PCa. We hypothesize that dAS involving exon 14 of FGFR3 is generating a shorter, more oncogenic variant in AA PCa, which is absent or weakly expressed in EA PCa. Differential splicing of FGFR3 in AA patients may be mechanisms contributing to AA PCa health disparities. Results: Cloning confirmed the presence of the FGFR3-L variant (containing exon 14) and the FGFR3-S variant (without exon 14) from EA and AA PCa cell lines, respectively. RNA-seq data analysis suggests decreased survival of PCa patients with high FGFR3-S/-L expression ratios. EA cell lines overexpressing FGFR3-S show increased small molecule inhibitor (SMI) TKI258-mediated resistance to proliferation, invasion, and apoptosis in vitro. Additionally, mice injected with cells overexpressing FGFR3-S have increased tumor growth, metastasis, and resistance to TKI258 treatment. Conclusions: We have identified an oncogene of interest, FGFR3, which undergoes exon skipping specific to AA PCa. We have successfully cloned this novel FGFR3 variant in cell lines and created stable cell lines overexpressing both short and long variants. In vitro and in vivo studies suggest FGFR3-S is more resistant to SMIs. Thus, dAS in FGFR3 may be one mechanism contributing to the increased aggressiveness of PCa in AA patients. Citation Format: Jacqueline Moy, Bi-Dar Wang, Norman H. Lee. Novel targeted therapy-resistant FGFR3 splice variant increases oncogenic phenotype in African American prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2637.