Prostate Cancer In African American Men Research Articles

Association of Anthropometric Measures with Prostate Cancer among African American Men in the NCI-Maryland Prostate Cancer Case-Control Study.

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.

Abstract B73: SOX2 regulation of FOXP1 as a mechanism driving disparate aggressiveness of prostate cancer in African-American men

Abstract Background: Although organ-confined, moderately graded prostate cancer has encouraging cure rates, progression to castration-resistant prostate cancer (CRPC) from advanced, high-grade lesions represents the lethal form of this malignancy, for which current therapeutic modalities are only palliative; patients with CRPC will die from their disease. Importantly, African-American (AA) men exhibit both a higher incidence of prostate cancer diagnoses and are at higher risk of developing CRPC as compared to other racial groups. Currently, the mechanisms driving prostate cancer disparities in AA men are poorly understood, and new biomarkers and novel drugs to address this disparity are in high demand to improve personalized medicine and clinical management of prostate cancer in AA men. Work by our group and others has identified SOX2 (sex determining region Y-box 2), an essential transcription factor for maintaining the survival and pluripotency of undifferentiated embryonic stem cells (ESCs), to be associated with aggressive prostate cancer and that the constitutive overexpression of SOX2 in a hormone-sensitive, SOX2-negative prostate cancer cell line is sufficient to generate a castration-resistant phenotype both in vitro and in vivo. Further, our data demonstrate canonical SOX2 transcriptional cofactors OCT4 and NANOG are frequently not expressed in prostate cancer, implying that SOX2 has unique, non-stem cell gene targets and binding partners within malignant prostate malignancies. Methods and Results: To elucidate such SOX2 gene targets in CRPC, we performed SOX2 chromatin immunoprecipitation and sequencing (ChIP-Seq) in prostate cancer cells, revealing SOX2 binding of several interesting and functionally important gene target promoters, including FOXP1, an AR target gene and transcription factor known to play a role in disparate aggressiveness of prostate cancer in African-American men. Based on these findings, we hypothesize that upon AR ablation in prostate cancer treatment, FOXP1, a tumor suppressor demonstrated to be associated with disparate prostate cancer aggressiveness in AA men, is repressed by SOX2 to drive CRPC in AA men. Work to test this hypothesis is currently under way, and includes (1) assessment of differential FOXP1 gene expression using MDA-PCa-2a, MDA-PCa-2b, and EA0066-hT, prostate cancer cell lines derived from AA men, and CWRR1, CWR22Rv1, and LNCaP, prostate cancer cell lines derived from CA men overexpressing SOX2 in the context of AR ablation; and (2) FOXP1 ChIP-Seq paired with RNA-Seq in tumor tissues prospectively collected from AA and CA men with prostate cancer undergoing radical prostatectomy. Conclusion: The work proposed herein represents an in-depth exploration of basic SOX2 biology in the context of CRPC, is highly innovative and translational, and has transformative potential to improve clinical patient management and eradicate disparities in CRPC. Note: This abstract was not presented at the conference. Citation Format: Anthony Williams, Larischa de Wet, Marc Gillard, Steve Kregel, Tzintzuni Garcia, Russell Szmulewitz, Don Vander Griend. SOX2 regulation of FOXP1 as a mechanism driving disparate aggressiveness of prostate cancer in African-American men [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B73.

Ethnic differences in TGFβ-signaling pathway may contribute to prostate cancer health disparity.

Epidemiological studies show that the incidence and mortality rates of prostate cancer (PCa) are significantly higher in African-American (AA) men when compared with Caucasian (CA) men in the United States. Transforming growth factor β (TGFβ) signaling pathway is linked to health disparities in AAs. Recent studies suggest a role of TGFβ3 in cancer metastases and its effect on the migratory and invasive behavior; however, its role in PCa in AA men has not been studied. We determined the circulating levels of TGFβ3 in AA and CA men diagnosed with PCa using ELISA. We analyzed serum samples from both AA and CA men diagnosed with and without PCa. We show that AA PCa patients had higher levels of TGFβ3 protein compared with AA controls and CA patients. In fact, TGFβ3 protein levels in serum were higher in AA men without PCa compared with the CA population, which may correlate with more aggressive disease seen in AA men. Studies on AA-derived PCa cell lines revealed that TGFβ3 protein levels were also higher in these cells compared with CA-derived PCa cell lines. Our studies also reveal that TGFβ does not inhibit cell proliferation in AA-derived PCa cell lines, but it does induce migration and invasion through activation of PI3K pathway. We suggest that increased TGFβ3 levels are responsible for development of aggressive PCa in AA patients as a consequence of development of resistance to inhibitory effects of TGFβ on cell proliferation and induction of invasive metastatic behavior.

Abstract B28: Baseline prostate-specific antigen (PSA) levels in midlife predict aggressive prostate cancer in African-American men

Abstract Background: Baseline prostate specific antigen (PSA) levels measured in midlife predict future prostate cancer mortality among white men. There are minimal data on whether a baseline PSA in African-American men, who experience the highest incidence and mortality of this disease, predicts future aggressive prostate cancer. Methods: We undertook a nested case-control study among African-American men age 40 to 64 years who gave prediagnostic blood at enrollment in the Southern Community Cohort Study between 2002-2009 and were followed a median of 9 years for cancer incidence and mortality through 2015. Baseline total and free PSA levels were available for 197 prostate cancer cases (55 aggressive cases, Gleason ≥4+3=7, AJCC Stage III or IV, or cancer-specific death) and 569 age-matched controls. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between baseline PSA levels and risk of total and aggressive prostate cancer. Results: Median PSA among controls was 0.72, 0.80, 0.94, and 1.03 ng/mL for men aged 40 to 49, 50 to 54, 55 to 59, and 60 to 64 years, respectively. Relative risk of total prostate cancer was strongly associated with baseline PSA levels in midlife: ORs (95% CIs) comparing PSA levels in the >90th percentile vs. ≤median were 93.7 (22.5-390) at 40 to 54 years and 77.0 (24.9-238) at 55 to 64 years. Risk of aggressive prostate cancer was also strongly associated with baseline PSA levels in midlife: ORs (95% CIs) comparing PSA levels in the >90th percentile vs. ≤median were 80.8 (14.7 to infinity) at 40-54 years Citation Format: Mark Preston, Travis Gerke, Sigrid V. Carlsson, Lisa Signorello, Daniel D. Sjoberg, Sarah C. Markt, Adam S. Kibel, Quoc-Dien Trinh, Mark Steinwandel, William Blot, Andrew J. Vickers, Hans Lilja, Lorelei A. Mucci, Kathryn M. Wilson. Baseline prostate-specific antigen (PSA) levels in midlife predict aggressive prostate cancer in African-American men [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B28.

Use of Prostate-Specific Antigen Velocity as a Screening Tool for Pre-Biopsy Detection of Prostate Cancer in African-American Men: A Single Institutional Analysis

Use of Prostate-Specific Antigen Velocity as a Screening Tool for Pre-Biopsy Detection of Prostate Cancer in African-American Men: A Single Institutional Analysis

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations.

African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n = 102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3% to 5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor-suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.Significance: Systematic genomic sequencing of prostate cancer in African-American men revealed new insights into prostate cancer, including the identification of ERF as a prostate cancer gene; somatic copy-number alteration differences; and uncommon PIK3CA and PTEN alterations. This study highlights the importance of inclusion of underrepresented minorities in cancer sequencing studies. Cancer Discov; 7(9); 973-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.

Abstract 5772: Developing a patient derived 3D co-culture model of prostate organoids to examine biological mechanisms involved in prostate cancer disparities

Abstract The prostate is composed of a fibro-muscular stromal and glandular epithelial cells. Cross-talk between these cell populations is essential for normal prostate development and is involved in carcinogenesis. In the past year, an estimated 220,800 new cases of prostate cancer (PCa) were diagnosed and 27,540 died of PCa. PCa in African American men occurs more frequently, develops at a much earlier age, and is more aggressive and lethal compared to men of European descent. Both biological and socioeconomic factors likely contribute to this disparity. There is currently a paucity of relevant preclinical models in which to examine biological mechanisms in African American PCa. Patient-derived organoids are a recently developed in vitro preclinical model which facilitate examination of underlying mechanisms of disease etiology. However, current models of epithelial organoid growth lack the prostate stroma. To address this unmet need, we began development of a 3D organoid model that incorporated both primary human prostatic epithelial (PrE) and stromal (PrS) cells to better mimic the microenvironment of the organ. Prostate organoids were derived from cells collected from radical prostatectomy tissues from patients (UIC IRBs: 2006-0679 (PI Behm), (2013-0341(PI Nonn). Mixtures of single PrE-derived and single PrS-derived cells were seeded in 3D in matrigel. Bright-field microscopy of live organoids and histological examination of fixed organoids showed that the addition of PrS cells to the culture altered the shape of the organoids compared to the spherical phenotype observed in PrE only cultures. Immunofluorescent analysis of the basal cell marker p63 showed increased epithelial differentiation in the co-culture organoids. In summary, these data suggest that inclusion of prostate stroma in co-culture organoid models influences prostatic epithelial organoid development in vitro. Ongoing studies are focused on molecular analysis or organoid phenotypes and comparison of AA and EA-derived organoids. Citation Format: Joseph Marsili, Zachary Richards, Jason Garcia, Cindy Voisine, Larisa Nonn. Developing a patient derived 3D co-culture model of prostate organoids to examine biological mechanisms involved in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5772. doi:10.1158/1538-7445.AM2017-5772

Trichomonas vaginalis infection and risk of prostate cancer: associations by disease aggressiveness and race/ethnicity in the PLCO Trial.

Results from previous sero-epidemiologic studies of Trichomonas vaginalis infection and prostate cancer (PCa) support a positive association between this sexually transmitted infection and aggressive PCa. However, findings from previous studies are not entirely consistent, and only one has investigated the possible relation between T. vaginalis seropositivity and PCa in African-American men who are at highest risk of both infection and PCa. Therefore, we examined this possible relation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, including separate analyses for aggressive PCa and African-American men. We included a sample of participants from a previous nested case-control study of PCa, as well as all additional Caucasian, aggressive, and African-American cases diagnosed since the previous study (total n=438 Gleason 7 Caucasian cases, 487 more advanced Caucasian cases (≥Gleason 8 or stage III/IV), 201 African-American cases, and 1216 controls). We tested baseline sera for T. vaginalis antibodies. No associations were observed for risk of Gleason 7 (odds ratio (OR)=0.87, 95% confidence interval (CI) 0.55-1.37) or more advanced (OR=0.90, 95% CI 0.58-1.38) PCa in Caucasian men, or for risk of any PCa (OR=1.06, 95% CI 0.67-1.68) in African-American men. Our findings do not support an association between T. vaginalis infection and PCa.

Abstract 1338: Exosome secretion promotes proliferation of African American prostate cancer cells under hypoxia: Role of HIF2A and RAB signaling

Abstract Background and Objectives: African American men experience worse prostate cancer (PCa) outcomes compared with those of Caucasian men not only in incidence and mortality rates but also harbor higher grade tumors compared to Caucasians. While the disparity is likely multifactorial, there may be biological basis for such phenomenon. Hypoxia in the tumor microenvironment is the key determinant of disease aggressiveness regulating primary growth, angiogenesis, metastasis and treatment outcomes. But role of hypoxia in the aggressiveness of PCa in African-American men has not been characterized yet. Here, we focused on hypoxia signaling, exosome biogenesis and characterization in African-American PCa cells compared to Caucasian PCa cells. Methods: We employed several techniques (cell viability assays, ultracentrifugation, nanoparticle tracking analyses [NTA], electron microscopy, and western blotting) to compare exosomes biogenesis and underlying molecular mechanisms in African-American and Caucasian PCa cells under normoxic and hypoxic conditions. Results: Compared to normoxic condition, African-American PCa cells (E006AA-hT and RC77T) either survived better or proliferated under hypoxia (1% O2), while growth of Caucasian PCa cells (PC3 and LNCaP) was strongly inhibited under hypoxia. NTA analyses showed that all PCa cells secreted more exosomes under hypoxia compared to normoxia, but more prominently in African-American PCa cells (E006AA-hT: 4.4 fold, RC77T: 35 fold, PC3: 3 fold and LNCaP: 2 fold). Exosomes secreted by E006AA-hT cells under hypoxia were loaded with higher amount of HSP70, HSP90, IL6 and Annexin II, and lower TGFβ. These exosomes also showed significantly higher MMP9 loading compared to E006AA-hT cell lysates. More importantly, under hypoxia, exosome biogenesis inhibition by GW4869 (20 µM) and 5-(N,N-dimethyl) amiloride (0.1-5 µg/ml) significantly reduced the E006AA-hT cell viability by 30% (p=0.0001) and 20-60% (p< 0.005 - 0.0001), respectively in 48 hrs. Further studies on hypoxia signaling revealed that E006AA-hT cells have significantly higher HIF2α and HIF1β but low HIF1α expression compared to LNCaP cells. Interestingly, HIF2α was present largely in nuclear fraction and its expression was similar under both normoxic and hypoxic conditions in E006AA-hT cells. Studies on the RAB and its effector proteins indicated that RabGAP5 expression was strongly increased under hypoxia in both E006AA-hT and LNCaP cells. Further, compared to LNCaP cells, E006AA-hT cells showed higher expression of Rab5 and Rabex5 but lower Rab4, and these molecules did not change significantly under hypoxia. Conclusion: African-American PCa cells have growth advantage under hypoxia mainly through higher exosome secretion; and higher expression/activity of HIF2α and RAB-signaling molecules could be associated with PCa aggressiveness in African-Americans. Citation Format: Gatikrushna Panigrahi, Taylor C. Peak, Sierra L. Patterson, Nicole Kasica, Ravi Singh, Ashok Hemal, Gagan Deep. Exosome secretion promotes proliferation of African American prostate cancer cells under hypoxia: Role of HIF2A and RAB signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1338. doi:10.1158/1538-7445.AM2017-1338

Is active surveillance a suitable option for African American men with prostate cancer? A systemic literature review.

Certain patients presenting with either low or very-low-risk prostate cancer (PCa) can represent a therapeutic dilemma for physicians. The oncologic outcomes of active surveillance (AS) for men with very-low-risk PCa are overall excellent. However, there are concerns about AS related to the potential for upgrading or upstaging. The African American (AA) population is under-represented in studies evaluating AS outcomes and this is particularly important because of the unique epidemiology of PCa in AA men. A literature review through the Medline database published from 1990 until August 2015 was performed to identify studies reporting outcomes of the AA population with low-risk PCa that underwent either AS or treatment. An additional search for studies on genetic mechanisms involved in development of PCa in AA men was also performed. Eleven studies on pathologic results of AA men who would qualify for AS were identified and in eight of these studies AA race was found to be associated with adverse pathological outcomes such as positive surgical margins, upgrading or upstaging. The other three studies reported no significance in these parameters with respect to race. Five more studies reported outcomes of AS in AA men with different study end points. AA men were mainly found to have a higher rate of disease reclassification subsequent to active treatment. The studies on genetic mechanisms also identified different genetic alterations in the AA population. AA men with clinically defined low-risk PCa may have either a higher grade or volume of cancer that was not detected on routine evaluation. Therefore, AS among such patients should be approached with caution. We recommend discussing such risks with AA patients with an acknowledgement that existing favorable outcomes noted in largely Caucasian populations may not be applicable to AA patients. We propose a modified evaluation plan for AA patients that includes an early confirmatory biopsy preceded by an magnetic resonance imaging to optimally detect occult cancer foci.

Meta-analysis of the role of IL-6 rs1800795 polymorphism in the susceptibility to prostate cancer: Evidence based on 17 studies.

Playing critical roles in immune responses, interleukin-6 (IL-6) has been proposed to be involved in the development of multiple cancers, including prostate cancer. The rs1800795 polymorphism in the promoter of the gene IL-6 can affect the transcription and expression of the gene, becoming a common target in association studies on tumors. We therefore carried out this meta-analysis to further discuss the relationship of this polymorphism with the risk of prostate cancer.Relevant publications were retrieved from the electronic databases. The strength of the correlation between IL-6 rs1800795 polymorphism and prostate cancer risk was evaluated using pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs). Q test was adopted to examine between-study heterogeneity, with P < 0.05 as significant level. Subgroup and meta-regression analyses were conducted to explore potential source of heterogeneity. Sensitivity analysis was implemented to test the statistical stability of the final results. In addition, funnel plot and Egger test were employed to inspect publication bias among included studies.A total of 13 132 cases and 15 282 controls were ultimately incorporated into the present study. Overall estimates revealed no significant relationship between IL-6 rs1800795 polymorphism and prostate cancer risk in total analysis, but a risk-increasing effect of the polymorphism was detected in African-American subgroup under CC versus GG and CC versus GG + GC contrasts (OR 3.43, 95% CI 1.01–11.71; OR 3.51, 95% CI 1.04–11.82) after subgroup analysis by ethnicity.IL-6 rs1800795 polymorphism may enhance the susceptibility to prostate cancer in African-American men.

Abstract B58: Single-nucleotide polymorphisms of race-related alternatively spliced genes associate with prostate cancer risk, aggressiveness and/or survival

Abstract Background: African American (AA) men exhibit nearly 2-fold higher incidence and 3-fold higher mortality rates from prostate cancer (PC) compared with white men. This disparity likely results from a complex interplay between behavioral, social, neighborhood and biological factors, which all work collectively to generate increased tumor aggressiveness in AAs. Recent data from our laboratory, evaluating human PC biopsy tissue led to the identification of alternative splicing events between AA and white PC that track with increased growth and more aggressive invasion characteristics of PC in AA men. In the present study, we explored associations between genetic variants of 30 such alternatively spliced genes and PC risk, aggressiveness and survival in white and AA groups by analyzing published genome-wide association studies (GWAS) of PC. Methods: We used GWAS datasets from the Multiethnic Cohort Study of Diet and Cancer (MEC), including AA PC cases and controls, and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), including white PC cases and controls, to evaluate associations of 11,073 and 10,385 single-nucleotide polymorphisms (SNPs), respectively, in 30 genes identified to be alternatively spliced between white and AA PC with PC risk, aggressiveness and survival. For risk, we evaluated 1150 cases and 1101 controls in PLCO and 670 cases and 658 controls in MEC, for aggressiveness, we evaluated 237 aggressive and 843 non-aggressive in PLCO and 234 aggressive and 436 non-aggressive in MEC, and for survival, we evaluated 1150 overall, 237 aggressive and 843 non-aggressive in PLCO. We then performed in silico bioinformatics to investigate potential functions of the SNPs. Results: Significant associations between SNPs in FN1, COL6A3 and ACACA and SNPs in SEMA3C and FASN and PC risk in white and AA populations, respectively, were identified. In addition, SNPs in ACACA and SNPs in SEMA3C, RELN, MYBPC1, NCOR2 and WDR4 were found to be significantly associated with PC aggressiveness in white and AA populations, respectively. Furthermore, significant associations between SNPs in RHOU, FN1, COL6A3, SEMA3C, RELN, CD44, LMO7 and WDR4 and PC survival in a white population were identified. All of the aforementioned SNPs were predicted to play a role in splicing regulation. Conclusions: SNPs of race-related alternatively spliced genes that are predicted to play a role in splicing regulation are significantly associated with PC risk, aggressiveness and/or survival in white and/or AA populations. Such variants have the potential to serve as novel molecular targets for development of biomarkers of increased risk of aggressive PC or therapeutics against aggressive PC. Ultimately, such biomarkers and therapeutic agents could serve as novel precision medicine interventions, reducing the mortality burden from PC among AA men. Citation Format: Jennifer Freedman, Yanru Wang, Hongliang Liu, Patricia Moorman, Terry Hyslop, Daniel George, Norman Lee, Qingyi Wei, Steven Patierno. Single-nucleotide polymorphisms of race-related alternatively spliced genes associate with prostate cancer risk, aggressiveness and/or survival. [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 B58.

Abstract B11: Proteomic analysis of serum-derived exosomes: Identification of novel protein signature associated with African-American prostate cancer

Abstract African-American men face a stark prostate cancer (PCA)-related health disparity in the United States, with the highest incidence and mortality rate compared to all other races. African-American men are more frequently diagnosed with high Gleason grade PCA at a younger age and with a poorer prognosis. In the past three decades, there has been little improvement in reducing this health disparity, demanding additional and innovative measures. Here, we focused on the identification of novel serum exosome-based ‘protein signature' for potential use in the early detection and better prognosis of PCA in African-American men. Analysis of clinical serum samples showed that compared to healthy individuals, exosome concentration was increased by ~3.2 fold (p=0.047) in the sera of African-American men with PCA (Gleason score 7). Mass spectrometry based proteomic analysis of serum exosomal proteins showed 55 common proteins in African-American men with PCA (PAA) and normal African-American men without PCA (NAA). Interestingly, 7 unique proteins [Isoform 2 of Coiled-coil and C2 domain-containing protein 1A, Keratin type I cytoskeletal 10, UPF0728 protein C10orf53, DnaJ homolog subfamily C member 13, Prothrombin, Apolipoprotein(a) and Coiled-coil domain-containing protein 172] were present only in PAA, and not in NAA. The top upregulated proteins in PAA, as compared to NAA, included Keratin type II cytoskeletal 2 epidermal (64 fold), Serum amyloid P-component (39 fold), Keratin type II cytoskeletal 1 (13 fold), Keratin type I cytoskeletal 9 (12 fold), Isoform 2 of Filamin-A (2.6 fold), Isoform 3 of Vitamin D-binding protein (2.4 fold), Ig kappa chain V-II region Cum (2.4 fold) and Isoform 2 of Eukaryotic translation initiation factor 2-alpha kinase 4 (1.8 fold). The top downregulated proteins in PAA included Apolipoprotein A-I (0.04 fold), Complement component C8 alpha chain (0.07 fold), Plasminogen (0.08 fold), Complement component C7 (0.1 fold), and Isoform 2 of Inter-alpha-trypsin inhibitor heavy chain H4 (0.2 fold). Importantly, Ingenuity pathway analysis (IPA) showed that the proteins detected by proteomic analysis in PAA exosomes belonged to the acute-phase response signaling pathway proteins, which have been reported for their potential use as diagnostic biomarkers for PCA. Next, we compared proteins loaded in PAA serum exosomes with Gleason score-matched Caucasian PCA (PCC) serum exosomes. PAA and PCC exosomes shared 57 common proteins, while PAA serum exosomes showed six unique proteins (Isoform 2 of Coiled-coil and C2 domain-containing protein 1A, UPF0728 protein C10orf53, Ig kappa chain V-I region EU, Ig kappa chain V-II region Cum, DnaJ homolog subfamily C member 13, Coiled-coil domain-containing protein 172). Furthermore, top upregulated proteins in PAA, as compared to PCC, included Isoform 2 of Eukaryotic translation initiation factor 2-alpha kinase 4 (34 fold), Keratin type I cytoskeletal 10 (10 fold), SCO-spondin (5.3 fold), Serum amyloid P-component (4 folds) and Apolipoprotein(a) (3.9 fold). The top down regulated proteins in PAA, as compared to PCC, included Ig lambda chain V-I region WAH (0.02 fold), alpha-1B-glycoprotein (0.03 fold), Apolipoprotein A-I (0.03 fold), Complement component C8 alpha chain (0.06 fold) and Isoform 2 of Haptoglobin (0.09 fold). Overall, we have identified several unique and differentially expressed proteins in the serum exosomes of African-American men with PCA. These results also support further development and application of serum exosome-based proteomic signature for early detection and better prognosis of PCA in African- American men. Citation Format: Gagan Deep, Gatikrushna Panigrahi, Rakesh Singh, Kathleen Torkko, Adrie Bokhoven. Proteomic analysis of serum-derived exosomes: Identification of novel protein signature associated with African-American prostate cancer. [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 B11.

Abstract B34: The Role of Pro-Inflammatory Cytokines in Prostate Cancer in African American Men

Abstract Background: African American men (AAM) have a 60% higher risk of being diagnosed with prostate cancer and a 2 to 3 times greater risk of dying from the disease compared to European American men (EAM). We previously reported evidence that there may be a molecular basis for these disparities from high-throughput gene expression analysis of PCa specimens, the data showed that pro-inflammatory cytokine signaling factors, including IL6 and TGFB1, are significantly upregulated and over-represented in PCa from AAM. Objective/Methods: the objective of our more recent research was to gain understanding of the role for IL6 in promoting aggressive prostate cancer in AAM. We used established cell lines derived from PCa from AAM and EAM to study if cancer cells produce IL6 and how IL6 impacts cancer cell phenotypes in vitro. We also conducted a pilot RNA-sequencing study to analyze aggressive PCa specimens and matched non-cancer adjacent prostate tissue for insights as to the role of the microenvironment and potential PCa-stroma crosstalk. Results: Results of our PCa cell line work indicate that a subpopulation of stem-cell like cancer cells produce IL6 and that IL6 acts in autocrine fashion to maintain that subpopulation. For the African American MDA-PCa2b cell line, IL6 expression was not detected. However, treatment of these cells with IL6 induced cancer stem cell-like prostasphere formation and growth. Results of our high-throughput gene expression analysis suggest that specifically for AAM, cancer cells are the source of pro-inflammatory cytokines in less aggressive cancer, but for aggressive prostate cancer pro-inflammatory cytokines originate from the non-cancer, prostate microenvironment. Conclusion: our mechanism studies in PCa-derived cell lines and high-throughput functional genomic analyses of human specimens converge to improve understanding of the molecular biology unique to aggressive PCa in AAM. Continued research and development is warranted to show how this knowledge could be used to improve clinical decision-making and patient outcomes. Citation Format: Aliccia B. Bollig-Fischer, Bin Bao, Christophe Legendre, Greg Dyson, Wael Sakr, John Carpten, Isaac Powell. The Role of Pro-Inflammatory Cytokines in Prostate Cancer 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 B34.

Abstract C66: Screening via multiple PSA measures to detect virulent prostate cancer could provide a way to address fundamental issues in African-American men's health

Abstract The dilemma facing individuals wishing to make decisions regarding prostate cancer (PrCA) screening pivots on two opposing outcomes: over-diagnosing indolent cancer and under-diagnosing virulent cancer. In conjunction with limited data on which to draw conclusions, this dilemma formed the basis on which the US Preventive Services Task Force made its decision to not recommend PSA screening. Data driving that decision-making process was derived nearly entirely from European and European-American men, even though African Americans are much more likely to be diagnosed with later-stage, more aggressive disease at younger ages. The discrepancy that we see between the US' highest-world-quintile incidence rates and second-lowest-world-quintile mortality rates may be explained entirely by the presence of high-virulence disease among African Americans. Clearly, detecting aggressive disease represents a significant public health issue and unmet clinical need. Development and discovery of biomarkers to predict PrCA that is likely to kill if left untreated is the major challenge in PrCA prevention and control. With this background in mind we sought to interrogate a large data set with multiple PSAs measured at regular (i.e., annual) intervals to see if we could predict high-virulence PrCA. Using the PLCO data we showed that with ≥three measures we were able to improve sensitivity and specificity of the PSA test to &amp;gt;97% overall and &amp;gt;99% among African-American men for detecting virulent, clinically relevant high-risk prostate cancer (PSA level ≥ 20ng/ml, cancer that invades prostate capsule, PrCA that involves more than one lobe, or Gleason score &amp;gt;7). At this juncture, we have begun to address the question of what can be done to distinguish aggressive PrCA in African-American men. We propose creating a cohort of 48,000 individuals who are willing to undergo annual PSA screening with the intention of validating/refining the algorithm that the University of South Carolina team developed using PLCO trial data that combines three or more PSA measures to detect virulent, high-risk PrCA. This cohort also would serve another important purpose. There currently exists no other cohort with a sufficient number of African-American men to address other important cancer-related health issues. So, if designed correctly, this cohort could serve numerous other purposes. This would be a simple follow-up study design with extensive baseline data collection and follow-up data collected at regular (i.e., annual) intervals. This would require strong community buy-in, commitment to providing information needed for informed decision-making, formulating rules for referring men out for diagnostic workup, and putting procedures in place for data linkage (e.g., to the cancer registries). Twelve institutions in 10 states across the US have expressed interest in being involved. Currently, there are two, non-mutually exclusive, options for recruitment. The Veterans Administration (VA) system could be ideal setting for this because: 1. They already have the screening infrastructure in place; 2. There isn't the financial incentive to over-diagnose and over-treat; 3. There is an excellent system of medical records; 4. There are many African-American veterans in the VA system; and 5. The medical home (for subsequent care) already is in place. The NCI's community oncology research program (NCORP) appears to understand the CBPR imperative. As such, they have good access to local, interested communities and in some regions of the country this includes large AA populations. They have excellent community relations and local “connectivity” that could help to ensure a competent, caring ‘medical home' that would be essential for program viability (i.e., recruitment and follow-up). Depending on geographical particulars, there could be good overlap with the VA. NCORPS could add an important element of academic medicine/ NCI imprimatur to the mix. Citation Format: James R. Hebert, Abraham Turner, Johnny Payne, Azza Shoaibi. Screening via multiple PSA measures to detect virulent prostate cancer could provide a way to address fundamental issues in African-American men's health. [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 C66.

Exosomes-based biomarker discovery for diagnosis and prognosis of prostate cancer.

African American men in the United States have higher incidence and mortality rates due to prostate cancer (PCa) compared to other races. In 2016 alone, nearly 30,000 cases of PCa in African American men were diagnosed and 4,450 men died from PCa. The underlying reasons for this health disparity in PCa are complex and include social, economic, and biologic determinants. To reduce or eliminate this health disparity, we must better understand the biology of the disease in African Americans and then develop novel diagnostic and prognostic biomarkers useful for timely and effective treatment decisions. Recently, there has been remarkable progress in understanding the role of exosomes (vesicles of 30-150 nm diameter) in cancer development and progression. Exosomes are loaded with unique cargo, including proteins, nucleic acids, lipids, and metabolites, that could predict the cells of their origin. Therefore, circulating exosomes in cancer patients are being used as a type of biopsy to identify novel biomarkers for early diagnosis, prognosis, and therapeutics. In this review, we discuss the promising use of exosomes to (a) identify race-related unique biological features of PCa, and (b) discover novel biomarkers for better diagnosis and prognosis of PCa, with the goal of reducing cancer health disparities.

Abstract 3434: Neighborhood obesogenic environment and the risk of prostate cancer: The Multiethnic Cohort

Abstract Background: Obesity is a potentially modifiable risk factor for advanced prostate cancer (PCa). However, the role of the neighborhood obesogenic environment, characterized by obesity-related built and social environment measures, has not been evaluated in relation to PCa risk. Objective: To examine the association of neighborhood obesogenic environment with PCa risk in African American (AA), Japanese American (JA), Latino (LA), and White (WH) men in the California component of the Multiethnic Cohort (MEC) Study. Method: Individual-level sociodemographic data and health behaviors were linked with neighborhood measures of built and social environment for 42,850 men in the MEC, who predominately live in Los Angeles County. A principal components factor analysis was used to create indices based on 10 measures—neighborhood SES, population density, total businesses, recreational facilities, retail food environment, restaurant environment, parks, street connectivity, commuting by car, and traffic density—resulting in 4 obesogenic environment indices: physically active, low SES urban, businesses density, and unhealthy food. During a mean follow-up of 15 years and through linkage to the California Cancer Registry, 4,775 incident PCa cases were identified. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between each index and PCa risk, overall and stratified by race/ethnicity and disease aggressiveness. For Latinos, additional stratified analyses were conducted by nativity. Results: Associations between the obesogenic indices and PCa risk varied by race/ethnicity. WH residing in low business environments experienced lower PCa risk (quintile [Q] 1 [low] vs. Q5 [high]: HR, 0.56 [95% CI, 0.41-0.77], p-trend: 0.0002). Among AA, unhealthy food environments were associated with greater risk of aggressive disease (advance stage or Gleason score &amp;gt; = 7) (more vs. no: HR, 1.36 [95% CI, 1.09-1.70], p-trend: 0.0026). Among LA, living in Hispanic enclaves was associated with reduced risk (Q3-5 [high] vs. Q1-2 [low]: HR, 0.86 [95% CI, 0.75-0.98]), but living in high business environments was associated with increased risk of PCa (Q1 [low] vs. Q5 [high]: HR, 1.35 [95% CI, 1.05-1.73], p-trend: 0.0002) for those born in the US (p-trend: 0.0059). Lower SES urban environments were associated with a decreased risk of non-aggressive disease among LA (Q5 [low] vs. Q1 [high]: HR, 0.78 [95% CI, 0.63-0.98], p-trend: 0.0026), and was more marked among foreign-born (p trend = 0.0074) than US-born (p trend = 0.1211). Conclusions: Built and social environment factors are associated with PCa risk, but their associations varied by race/ethnicity, nativity (among LA), and disease aggressiveness. An unhealthy food environment was strongly associated with the risk of aggressive prostate cancer in AA men, warranting further investigation into the underlying mechanisms. Citation Format: Li Tao, Scarlett L. Gomez, Salma Shariff-Marco, Juan Yang, Song Yi Park, Cheryl Albright, Kristine Monroe, Brian Henderson, Laurence Kolonel, Loic Le Marchand, Lynne Wilkens, Iona Cheng. Neighborhood obesogenic environment and the risk of prostate cancer: The Multiethnic Cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3434.

Abstract 1776: Aspirin use among African American men reduces prostate cancer risk: Findings from the NCI-Maryland Prostate Cancer Case-Control study

Abstract Prostate cancer is a leading cause of cancer death in US men. Yet, the etiology of prostate cancer remains poorly understood, with only older age, African ancestry, family history of the disease, and multiple germline genetic variations being established disease risk factors. Prostate cancer occurs more often in African-American men and Caribbean men of African descent than in men of other race/ethnicities. The causes of these racial and ethnic differences are multifactorial, but it has been proposed that differences in tumor biology contribute to the health disparity associated with prostate cancer. Previously, our laboratory discovered immunobiology differences between African-American and European-American men where genes involved in the inflammatory response tended to be up-regulated in tumors of African American patients. Accumulating evidence suggests that inflammation may be involved in prostate carcinogenesis. Given these observations, we hypothesized that inflammation may contribute to prostate cancer risk and the survival health disparity observed between African-Americans and European-Americans. To this end, we conducted a case-control study in the greater Baltimore area where we recruited 1000 cases and 1000 controls composed of equal populations of African-American and European-American men. In our survey, we asked about non-steroidal anti-inflammatory drugs (NSAIDs) use categorized into aspirin, Tylenol, and other pain relievers that neither contain Tylenol nor aspirin. We found a significant association between aspirin use and prostate cancer risk—where aspirin use decreased the risk of prostate cancer. Strikingly, the decreased prostate cancer risk as a result of aspirin use was most profound in African-American men. We were also able to measure the levels of C-reactive protein, a marker for inflammation, to further evaluate the relationship between aspirin use, inflammation, and prostate cancer risk. Indeed, we did observe a decrease in C-reactive protein in patients who took aspirin. Interestingly, overall levels in healthy controls and prostate cases were higher in African-American subjects and patients when compared to European-Americans. Although aspirin use decreased C-reactive protein levels in African-American and European-American cases, African-Americans had significantly higher levels of C-reactive protein. The robust association between aspirin consumption and prostate cancer risk suggests that inflammation might be a driver in prostate cancer of African-American men. Additionally, the increased levels of C-reactive protein in African-American controls and cases might contribute to the excessive disease risk and mortality among these men. Citation Format: Cheryl J. Smith, Symone Jordan, Tiffany H. Dorsey, Dean Mann, Chris A. Loffredo, Elise Bowman, Wei Tang, Stefan Ambs. Aspirin use among African American men reduces prostate cancer risk: Findings from the NCI-Maryland Prostate Cancer Case-Control study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1776.

Hereditary cancer syndromes and prostate cancer development among African American men: The importance of complete family cancer history.

e16625Background: African American (AA) men are at increased risk for developing and dying from prostate cancer (PC). While family history PC has been recognized to raise the risk for PC in AA men,...

Clinical Use of PCA3 and TMPRSS2:ERG Urinary Biomarkers in African-American Men Undergoing Prostate Biopsy

Prostate specific antigen has decreased performance characteristics for the detection of prostate cancer in African-American men. We evaluated urinary PCA3 and TMPRSS2:ERG in a racially diverse group of men. After institutional review board approval, post-examination urine was prospectively collected before prostate biopsy. PCA3 and TMPRSS2:ERG RNA copies were quantified using transcription mediated amplification assays (Hologic, San Diego, California). Prediction models were created using standard of care variables (age, race, family history, prior biopsy, abnormal digital rectal examination) plus prostate specific antigen. Decision curve analysis was performed to compare the net benefit of PCA3 and TMPRSS2:ERG. Of 304 patients 182 (60%) were African-American and 139 (46%) were diagnosed with prostate cancer (69% African-American). PCA3 and TMPRSS2:ERG scores were greater in men with prostate cancer, 3 or more cores, 33.3% or more cores, greater than 50% involvement of greatest biopsy core and Epstein significant prostate cancer (p <0.01). PCA3 added to the standard of care plus prostate specific antigen model for the detection of any prostate cancer in the overall cohort (0.747 vs 0.677, p <0.0001) in African-American men only (0.711 vs 0.638, p=0.0002) and nonAfrican-American men (0.781 vs 0.732, p=0.0016). PCA3 added to the model for the prediction of high grade prostate cancer for the overall cohort (0.804 vs 0.78, p=0.0002) and African-American men only (0.759 vs 0.717, p=0.0003) but not nonAfrican-American men. Decision curve analysis demonstrated improvement with the addition of PCA3. ForAfrican-American men TMPRSS2:ERG did not improve concordance statistics for the detection of prostate cancer. For African-American men urinary PCA3 improves the ability to predict the presence of any and high grade prostate cancer. However, the TMPRSS2:ERG urinary assay does not add significantly to standard tools.