African American Prostate Cancer Cases Research Articles

Abstract C098: CYR61 expression in prostate cancer patients at City of Hope

Abstract In the US, African-American (AA) and Hispanic/Latino (H/L) men have higher rates of advanced prostate cancer (PCa), increased PCa-specific mortality, and are more likely to undergo metastasis than non-Hispanic White (NHW) men attributed to a lack of access to early screening, and a higher prevalence of risk factors such as obesity, diet, and genetic differences. Consequently, effective treatment of advanced PCa and elimination of racial and ethnic disparities for this malignancy require the identification of mechanisms of disease progression. In PCa, the cysteine-rich angiogenic inducer 61 (CYR61) contributes to malignant cell growth through interactions with extracellular ligands, such as integrins avb3 and a6b4. In previous studies, we have found that CYR61 is upregulated in metastatic PCa cell lines and knockdown of this protein significantly reduced metastatic cell proliferation, viability, prostasphere formation, and activation of the PI3/AKT pathway, indicating a potential utilization of CYR61 inhibition in the therapy of metastatic PCa. Interestingly, we have observed that in metastatic PCa cell models, IGF1 induction increased CYR61 protein expression. However, the correlation between PCa aggressiveness and levels of CYR61 in tumor-derived tissues from patients is poorly studied. Our goal with this study is to identify possible correlations in CYR61 expression that may reflect health disparities in PCa outcomes. We used in silico analyses from whole exome paired tumor/normal DNA sequencing and tumor RNA sequencing data available on 542 PCa cases in the City of Hope POSEIDON database to determine whether gene expression of CYR61 and IGF1 was correlated with genetic ancestry, Gleason score, and tumor purity. In univariate analyses, we found that H/L PCa cases had significantly higher levels of expression of CYR61 than NHW PCa cases (p = 0.043) and that both H/L and AA PCa cases had higher IGF1 expression levels, although only significant in AA (p=0.031). We also found that PCa patients with Gleason scores of 8 and higher had significantly lower expression of IGF1 than those with Gleason scores of 7 or less (p=0.006). Both CYR61 and IGF1 expression levels were significantly lower in those with luminal B (p=0.00000000053, p=0.000009, respectively) and with basal subtypes (p=0.00035, p=0.000069, respectively compared to luminal A subtype. Tumor purity was estimated by RNA-seq based on 141 genes specific to stroma and 141 genes specific to immune cells. CYR61 expression was significantly correlated with stromal and immune infiltration. These results suggest that reduced CYR61 expression is associated with more aggressive PCa. Additional analyses are ongoing to understand the interplay of variables of race and ethnicity, age, Gleason score, and tumor purity and to investigate outcomes of biochemical recurrence and death from PCa. Citation Format: Greisha L. Ortiz-Hernandez, Yuan Chun Ding, Susan L. Neuhausen. CYR61 expression in prostate cancer patients at City of Hope [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C098.

Germline mutations in DNA damage repair genes and HOXB13 among African American men diagnosed with early-onset prostate cancer.

10505 Background: Inherited defects in DNA damage repair (DDR) genes (e.g. ATM, BRCA1/2) and the tumor suppresser gene HOXB13 are rare in the general population, but have been observed at a higher rate among men with early-onset and advanced prostate cancer. However, most studies include few, if any, African American men, highlighting the need to understand the contribution of mutations in these genes in this high-risk population. Methods: A population-based cohort of 757 African American men diagnosed with prostate cancer at age 62 years or younger were identified and enrolled through the Metropolitan Detroit Cancer Surveillance System (MDCSS), one of NCI’s founding members of the SEER program. Participants completed a short survey to collect information on family history, medical history (including cancer-related treatment), surveillance, and health behaviors. Each participant submitted a saliva or blood sample for genetic analyses and consent for tumor tissue if available. All clinical data were collected through linkage with the MDCSS registry. Full exome sequencing was performed and herein, we report the mutation patterns observed in a panel of DNA repair genes and HOXB13. All variants were ranked according to frequency (MAF < 1%); REVEL, SIFT and PolyPhen scores for pathogenic potential; evidence from existing literature; and prevalence in the cohort. Results: Among the 744 African American prostate cancer cases with adequate DNA for sequencing and thus included in this analysis, the mean age at diagnosis was 55.6 years, 29% reported a family history of prostate cancer in a first degree family member, and 40% were initially diagnosed with intermediate- to high-risk disease (stage T3/T4 and/or Gleason 4+3 and higher at diagnosis). We identified 20 variants that were either known or predicted to be pathogenic in 11 candidate genes ( ATM, ATR, BRCA1/2, BRIP1, CHEK2, FANCA, HOXB13, MSH2, PALB2, and PMS2). These particular variants were more common among men diagnosed before age 55 and in men with high grade cancer in this cohort. Conclusions: Our results suggest that mutations in DDR genes and HOXB13 may be important cancer risk factors for African American men diagnosed with early-onset and intermediate- to high-risk disease. Further study is necessary to describe the spectrum and prevalence of genetic mutations in this population including the characterization of variants of unknown significance.

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.

Impact of individual and neighborhood factors on disparities in prostate cancer survival

BackgroundWe addressed the hypothesis that individual-level factors act jointly with social and built environment factors to influence overall survival for men with prostate cancer and contribute to racial/ethnic and socioeconomic (SES) survival disparities. MethodsWe analyzed multi-level data, combining (1) individual-level data from the California Collaborative Prostate Cancer Study, a population-based study of non-Hispanic White (NHW), Hispanic, and African American prostate cancer cases (N = 1800) diagnosed from 1997 to 2003, with (2) data on neighborhood SES (nSES) and social and built environment factors from the California Neighborhoods Data System, and (3) data on tumor characteristics, treatment and follow-up through 2009 from the California Cancer Registry. Multivariable, stage-stratified Cox proportional hazards regression models with cluster adjustments were used to assess education and nSES main and joint effects on overall survival, before and after adjustment for social and built environment factors. ResultsAfrican American men had worse survival than NHW men, which was attenuated by nSES. Increased risk of death was associated with residence in lower SES neighborhoods (quintile 1 (lowest nSES) vs. 5: HR = 1.56, 95% CI: 1.11–2.19) and lower education (<high school vs. college: HR = 1.32, 95% CI: 1.05–1.67), and a joint association of low education and low nSES was observed. Adjustment for behavioral, hospital, and restaurant and food environment characteristics only slightly attenuated these associations between SES and survival. ConclusionBoth individual- and contextual-level SES influence overall survival of men with prostate cancer. Additional research is needed to identify the mechanisms underlying these robust associations.

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 C18: ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine

Abstract Introduction: Prostate cancer incidence and associated mortality is highest in African American men in comparison to other ethnicities. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different biochemical pathways of prostate carcinogenesis between African American and Caucasian men. Emerging observations of the ethnic differences of the ERG oncogenic activation, the most common prostate cancer genomic alteration described in Western countries, provides new insights into the ERG based stratification of prostate cancers in the context of the increasingly diverse ethnic patient populations in The United States. This rapidly advancing knowledge has potential to stratify prostate cancers by ERG typing in a given patient population that may eventually lead to new targeted treatments. Experimental procedures: For the comparative evaluation of ERG frequencies, ERG oncoprotein expression was analyzed in whole-mounted sections of 91 Caucasian American and 91 African American prostate cancer cases matched for age, Gleason score and pathologic stage. To evaluate the association of high grade tumors with ERG status prostate cancer specimens with a primary Gleason pattern of 4 or 5 or cumulative Gleason score of 8-10 from a total of 63 African American patients and 63 Caucasian American patients matched for age. For the comprehensive evaluation of ERG frequencies in African American patients we have examined 306 whole mounted prostate specimens representing hormone naïve cases with a minimum of two years of follow up after radical prostatectomy. ERG oncoprotein was evaluated by immunohistochemistry in all cases and the genomic rearrangement of the ERG gene was assessed in selected cases by FISH assy. Results: Markedly greater frequencies of ERG oncoprotein expression was noted in the index tumors of the Caucasian Americans (63.3%) compared to the African Americans (28.6%). The observed difference was even more pronounced in higher grade disease indicating significantly lower ERG frequencies among African American (16%) patients in comparison to Caucasian American men (49%). Comprehensive evaluation of ERG frequencies revealed that ERG positive tumors were more likely to be present in index tumors of younger African American men, whereas, ERG negative tumors were significantly associated with higher pathologic T stage when all tumors were assessed. Conclusions: ERG-based stratification defines molecular subtypes of prostate cancers. Association of ERG negative status with high grade tumors and poor prognostic features in African American patients warrants the development of informative marker panels that includes ERG to aid in diagnostic, prognostic and targeted therapy settings. The results of the present study underscore that typing prostate cancers for ERG significantly contributes to the understanding of causal alterations resulting in higher incidence and associated mortality among African American prostate cancer patients. Citation Format: Albert Dobi, Philip Rosen, James Farrell, Michael Degon, Denise Young, Sudhir Srivastava, Jacob Kagan, Gyorgy Petrovics, Jennifer Cullen, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava. ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C18. doi:10.1158/1538-7755.DISP13-C18

Fine-mapping IGF1 and prostate cancer risk in African Americans: the multiethnic cohort study.

Genetic variation at insulin-like growth factor 1 (IGF1) has been linked to prostate cancer risk. However, the specific predisposing variants have not been identified. In this study, we fine-mapped the IGF1 locus for prostate cancer risk in African Americans. We conducted targeted Roche GS-Junior 454 resequencing of a 156-kb region of IGF1 in 80 African American aggressive prostate cancer cases. Three hundred and thirty-four IGF1 SNPs were examined for their association with prostate cancer risk in 1,000 African American prostate cancer cases and 991 controls. The top associated SNP in African Americans, rs148371593, was examined in an additional 3,465 prostate cancer cases and 3,425 controls of non-African American ancestry-European Americans, Japanese Americans, Latinos, and Native Hawaiians. The overall association of 334 IGF1 SNPs and prostate cancer risk was assessed using logistic kernel-machine methods. The association between each SNP and prostate cancer risk was evaluated through unconditional logistic regression. A false discovery rate threshold of q < 0.1 was used to determine statistical significance of associations. We identified 8 novel IGF1 SNPs. The cumulative effect of the 334 IGF1 SNPs was not associated with prostate cancer risk (P = 0.13) in African Americans. Twenty SNPs were nominally associated with prostate cancer at P < 0.05. The top associated SNP among African Americans, rs148371593 [minor allele frequency (MAF) = 0.03; P = 0.0014; q > 0.1], did not reach our criterion of statistical significance. This polymorphism was rare in non-African Americans (MAF < 0.003) and was not associated with prostate cancer risk (P = 0.98). Our findings do not support the role of IGF1 variants and prostate cancer risk among African Americans.

Performance of the Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) tumor biomarker for identifying recurrent disease in African American patients.

Evaluation of prostate cancer prognosis after surgery is increasingly relying upon genomic analyses of tumor DNA. We assessed the ability of the biomarker panel Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) to predict biochemical recurrence in 33 European American and 28 African American prostate cancer cases using genome-wide copy number data from a previous study. "Biomarker positive" was defined as ≥20% of the 38 constituent copy number gain/loss GEMCaP loci affected in a given tumor; based on this threshold, the frequency of a positive biomarker was significantly lower in African Americans (n = 2; 7%) than European Americans (n = 11; 33%; P = 0.013). GEMCaP positivity was associated with risk of recurrence [hazard ratio (HR), 5.92; 95% confidence interval (CI), 2.32-15.11; P = 3 × 10(-4)] in the full sample and among European Americans (HR, 3.45; 95% CI, 1.13-10.51; P = 0.032) but was not estimable in African Americans due to the low rate of GEMCaP positivity. Overall, the GEMCaP recurrence positive predictive value (PPV) was 85%; in African Americans, PPV was 100%. When we expanded the definition of loss to include copy-neutral loss of heterozygosity (i.e., loss of one allele with concomitant duplication of the other), recurrence PPV was 83% for European American subjects. Under this definition, 5 African American subjects had a positive GEMCaP test value; 4 went on to develop biochemical recurrence (PPV = 80%). Our results suggest that the GEMCaP biomarker set could be an effective predictor for both European American and African American men diagnosed with localized prostate cancer who may benefit from immediate aggressive therapy after radical prostatectomy.

Gene-environment interactions between JAZF1 and occupational and household lead exposure in prostate cancer among African American men.

A single nucleotide polymorphism, rs10486567, in JAZF1 has consistently been associated with increased risk of prostate cancer. The physical interaction of zinc finger proteins, such as JAZF1, with heavy metals may play a role in carcinogenesis. This study assessed potential gene-environment statistical interactions (G×E) between rs10486567 and heavy metals in prostate cancer. In a case-only study of 228 African American prostate cancer cases, G×E between rs10486567 and sources of cadmium and lead (Pb) were assessed. Unconditional logistic regression was used to estimate interaction odds ratios (IORs), and generalized estimating equations were used for models containing nested data. Case-control validation of IORs was performed, using 82 controls frequency matched to cases on age-race. Among cases, a potential G×E interaction was observed between rs10486567 CC genotype and living in a Census tract with a high proportion of housing built before 1950, a proxy for household Pb exposure, when compared to CT or TT carriers (OR 1.81; 95% CI 1.04-3.16; p = 0.036). A stronger G×E interaction was observed when both housing and occupational Pb exposure were taken into account (OR 2.62; 95% CI 1.03-6.68; p = 0.04). Case-control stratified analyses showed the odds of being a CC carrier were higher in cases compared to controls among men living in areas with older housing (OR 2.03; CI 0.99-4.19; p = 0.05) or having high occupational Pb exposure (OR 2.50; CI 1.01-6.18; p = 0.05). In African American men, the association between JAZF1 rs10486567 and prostate cancer may be modified by exposure to heavy metals such as Pb.

MP41-02 CLINICAL AND PATHOLOGIC CHARACTERIZATION OF ERG EXPRESSION AND TESTOSTERONE IN AFRICAN AMERICANS

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2014MP41-02 CLINICAL AND PATHOLOGIC CHARACTERIZATION OF ERG EXPRESSION AND TESTOSTERONE IN AFRICAN AMERICANS Michael Degon, Denise Young, Yongmei Chen, Gyorgy Petrovics, Jennifer Cullen, Jacob Kagan, Sudhir Srivastava, David McLeod, Albert Dobi, Isabell Sesterhenn, and Shiv Srivastava Michael DegonMichael Degon More articles by this author , Denise YoungDenise Young More articles by this author , Yongmei ChenYongmei Chen More articles by this author , Gyorgy PetrovicsGyorgy Petrovics More articles by this author , Jennifer CullenJennifer Cullen More articles by this author , Jacob KaganJacob Kagan More articles by this author , Sudhir SrivastavaSudhir Srivastava More articles by this author , David McLeodDavid McLeod More articles by this author , Albert DobiAlbert Dobi More articles by this author , Isabell SesterhennIsabell Sesterhenn More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1219AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives African-American men are more likely to be diagnosed with prostate cancer and more likely to die from prostate cancer then Caucasian Americans prompting intense research for determining causal molecular alterations. In recent years substantial progress has been made in defining the causal role and prevalence of ERG oncogene in prostate tumorigenesis. However, only limited number of studies has examined the frequencies of ERG in African American prostate cancer cases. The objective of the current study is to determine ERG oncoprotein frequencies and correlation with patient demographics, tumor pathology, cancer progression, and biochemical recurrence in prostatectomy specimens of African-American men. Methods In this study we have included hormone naïve African-American prostate cancer patients presenting for radical prostatectomy at a single institution over an 18 year period with 2 years of follow up. Whole-mounted radical prostatectomy specimens from 306 African-American men were evaluated by immunohistochemistry with the mouse monoclonal anti-ERG antibody, 9FY. These results were then correlated with clinical and pathologic variables. Results Consistent with previous reports from our laboratory and from others, frequencies of ERG oncoprotein were 26% in index tumors and 48% when any tumors were ERG positive in a whole-mounted section. We have found that ERG positive tumors were more likely present in younger African-American men. ERG positive tumors were significantly enriched in lower grade tumors, and ERG positive tumors correlated with higher testosterone levels. Conclusions ERG positivity of index tumors correlates with higher testosterone levels and younger age at radical prostatectomy in African-Americans. Furthermore, higher nuclear grade is more frequent in ERG positive tumors. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e450-e451 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Michael Degon More articles by this author Denise Young More articles by this author Yongmei Chen More articles by this author Gyorgy Petrovics More articles by this author Jennifer Cullen More articles by this author Jacob Kagan More articles by this author Sudhir Srivastava More articles by this author David McLeod More articles by this author Albert Dobi More articles by this author Isabell Sesterhenn More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP41-03 NOTCH SIGNALING PATHWAY AS COMMON TARGET OF ERG IN DIVERSE TUMOR CELL TYPES

research for determining causal molecular alterations. In recent years substantial progress has been made in defining the causal role and prevalence of ERG oncogene in prostate tumorigenesis. However, only limited number of studies has examined the frequencies of ERG in African American prostate cancer cases. The objective of the current study is to determine ERG oncoprotein frequencies and correlation with patient demographics, tumor pathology, cancer progression, and biochemical recurrence in prostatectomy specimens of African-American men. METHODS: In this study we have included hormone na€ive African-American prostate cancer patients presenting for radical prostatectomy at a single institution over an 18 year period with 2 years of follow up. Whole-mounted radical prostatectomy specimens from 306 African-American men were evaluated by immunohistochemistry with the mouse monoclonal anti-ERG antibody, 9FY. These results were then correlated with clinical and pathologic variables. RESULTS: Consistent with previous reports from our laboratory and from others, frequencies of ERG oncoprotein were 26% in index tumors and 48% when any tumors were ERG positive in a wholemounted section. We have found that ERG positive tumors were more likely present in younger African-American men. ERG positive tumors were significantly enriched in lower grade tumors, and ERG positive tumors correlated with higher testosterone levels. CONCLUSIONS: ERG positivity of index tumors correlates with higher testosterone levels and younger age at radical prostatectomy in African-Americans. Furthermore, higher nuclear grade is more frequent in ERG positive tumors.

MP41-05 DELINEATION OF THE BIOLOGICAL LINK BETWEEN THE ERG SPLICE VARIANT, ERG8, AND ITS PROGNOSTIC FEATURES

research for determining causal molecular alterations. In recent years substantial progress has been made in defining the causal role and prevalence of ERG oncogene in prostate tumorigenesis. However, only limited number of studies has examined the frequencies of ERG in African American prostate cancer cases. The objective of the current study is to determine ERG oncoprotein frequencies and correlation with patient demographics, tumor pathology, cancer progression, and biochemical recurrence in prostatectomy specimens of African-American men. METHODS: In this study we have included hormone na€ive African-American prostate cancer patients presenting for radical prostatectomy at a single institution over an 18 year period with 2 years of follow up. Whole-mounted radical prostatectomy specimens from 306 African-American men were evaluated by immunohistochemistry with the mouse monoclonal anti-ERG antibody, 9FY. These results were then correlated with clinical and pathologic variables. RESULTS: Consistent with previous reports from our laboratory and from others, frequencies of ERG oncoprotein were 26% in index tumors and 48% when any tumors were ERG positive in a wholemounted section. We have found that ERG positive tumors were more likely present in younger African-American men. ERG positive tumors were significantly enriched in lower grade tumors, and ERG positive tumors correlated with higher testosterone levels. CONCLUSIONS: ERG positivity of index tumors correlates with higher testosterone levels and younger age at radical prostatectomy in African-Americans. Furthermore, higher nuclear grade is more frequent in ERG positive tumors.

Relationship of Early-Onset Baldness to Prostate Cancer in African-American Men

Early-onset baldness has been linked to prostate cancer; however, little is known about this relationship in African-Americans who are at elevated prostate cancer risk. We recruited 219 African-American controls and 318 African-American prostate cancer cases. We determined age-stratified associations of baldness with prostate cancer occurrence and severity defined by high stage (T3/T4) or high grade (Gleason 7+.) Associations of androgen metabolism genotypes (CYP3A4, CYP3A5, CYP3A43, AR-CAG, SRD5A2 A49T, and SRD5A2 V89L), family history, alcohol intake, and smoking were examined by baldness status and age group by using multivariable logistic regression models. Baldness was associated with odds of prostate cancer [OR = 1.69; 95% confidence interval (CI), 1.05-2.74]. Frontal baldness was associated with high-stage (OR = 2.61; 95% CI, 1.10-6.18) and high-grade (OR = 2.20; 95% CI, 1.05-4.61) tumors. For men diagnosed less than the age of 60 years, frontal baldness was associated with high stage (OR = 6.51; 95% CI, 2.11-20.06) and high grade (OR = 4.23; 95% CI, 1.47-12.14). We also observed a suggestion of an interaction among smoking, median age, and any baldness (P = 0.02). We observed significant associations between early-onset baldness and prostate cancer in African-American men. Interactions with age and smoking were suggested in these associations. Studies are needed to investigate the mechanisms influencing the relationship between baldness and prostate cancer in African-American men. African-American men present with unique risk factors including baldness patterns that may contribute to prostate cancer disparities.

Calcium intake and prostate cancer among African Americans: Effect modification by vitamin D receptor calcium absorption genotype

High dietary intake of calcium has been classified as a probable cause of prostate cancer, although the mechanism underlying the association between dietary calcium and prostate cancer risk is unclear. The vitamin D receptor (VDR) is a key regulator of calcium absorption. In the small intestine, VDR expression is regulated by the CDX-2 transcription factor, which binds a polymorphic site in the VDR gene promoter. We examined VDR Cdx2 genotype and calcium intake, assessed by a food frequency questionnaire, in 533 African-American prostate cancer cases (256 with advanced stage at diagnosis, 277 with localized stage) and 250 African-American controls who participated in the California Collaborative Prostate Cancer Study. We examined the effects of genotype, calcium intake, and diet-gene interactions by conditional logistic regression. Compared with men in the lowest quartile of calcium intake, men in the highest quartile had an approximately twofold increased risk of localized and advanced prostate cancer (odds ratio [OR] = 2.20, 95% confidence interval [CI] = 1.40, 3.46), with a significant dose-response. Poor absorbers of calcium (VDR Cdx2 GG genotype) had a significantly lower risk of advanced prostate cancer (OR = 0.41, 95% CI = 0.19, 0.90). The gene-calcium interaction was statistically significant (p = 0.03). Among men with calcium intake below the median (680 mg/day), carriers of the G allele had an approximately 50% decreased risk compared with men with the AA genotype. These findings suggest a link between prostate cancer risk and high intestinal absorption of calcium.

Abstract 2776: Prostate cancer and dietary calcium: Effect modification by the vitamin D receptor Cdx-2 polymorphism in the California Collaborative Prostate Cancer Study

Abstract Background: Calcium is classified as a probable cause of prostate cancer by the World Cancer Research Fund. We previously showed that the relationship between dietary calcium intake and prostate cancer risk was modified by a the vitamin D receptor, Cdx-2 polymorphism among African Americans. The high absorption A allele increases calcium absorption and is common among African Americans. The A alleles is less common among Caucasians, who have a lower incidence of prostate cancer compared to African Americans. Methods: We examined Caucasian and African American prostate cancer cases and controls from the California Collaborative Prostate Cancer Study. Of 1854 cases, 1140 were advanced stage at diagnosis and 714 were localized; 500 were African American and 1354 were Caucasian. Dietary calcium was assessed from a 74-item modified Block food frequency questionnaire. The VDR Cdx-2 genotype was measured by TaqMan assay. Main effects of genotype and of dietary calcium, and diet-gene interactions were estimated using conditional logistic regression, adjusting for study site (Northern/Southern California), Hispanic ancestry, socio-economic status, age, and family history of prostate cancer. Results: Analysis of race-specific quartiles of calcium intake showed that intake of more than 680 mg/day (above the median for African Americans or above the first quartile for whites) was associated with increased prostate cancer risk (odds ratio 1.48, 95% confidence interval 1.25 – 1.77). The effect of calcium intake on risk of advanced (but not localized) prostate cancer was modified by the VDR Cdx-2 genotype for both African Americans and whites. High calcium intake (&amp;gt;680 mg/day) was significantly associated with increased risk only among those with the VDR Cdx-2 GG low calcium absorption genotype (OR=1.90, 95% CI 1.40 – 2.57). High absorption genotypes (GA and AA) were associated with increased risk only among those consuming less than 680 mg/day of calcium. Odds ratios were 1.24 (95% CI: 0.82 – 1.87) for genotype GA and 1.69 (95% CI: 1.05 – 2.74) for genotype AA compared to genotype GG. Conclusions: Our findings suggest that genetically-determined high calcium absorption among African Americans could contribute to racial ethnic disparities in prostate cancer incidence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2776. doi:10.1158/1538-7445.AM2011-2776

Abstract A78: Modifiers of serum vitamin D and prostate cancer risk in African Americans

Abstract Background/Objective: Prostate cancer (PCa) is the most commonly diagnosed cancer among males in the United States. Compared to European American males, African American (AA) males are at increased risk for PCa and tend to have a more aggressive form of the disease. Recent laboratory studies have suggested deficiencies in vitamin D to be related with PCa risk. Serum levels of 25-hydroxyvitamin D [25(OH)D] are considered the best indicators of an individual's overall vitamin D status. However, vitamin D metabolism and physiology are modified by genetic and environmental factors such as ultraviolet radiation (UVR), skin color, diet, body mass index (BMI) and genes involved in vitamin D synthesis. The goal of this project is to study modifiers of serum 25(OH)D levels in order to improve our understanding of the role vitamin D plays on prostate cancer susceptibility in African Americans. Methods: This case-control study consisted of AA men (N=250) accrued from a university hospital in Washington, DC. Serum levels of 25(OH)D and prostate specific antigen (PSA) levels were assessed. BMI was calculated as weight/height2 (kg/m2). Study participants completed UVR exposure and food frequency questionnaires. Skin color was measured using a reflectance meter. Logistic regression models were used to test for associations between 25(OH)D levels and PCa risk, adjusting for ancestry, age, skin pigmentation, dietary vitamin D, supplemental vitamin D, sun exposure, and other lifestyle factors. In addition, we used linear regression models to explore determinants of serum 25(OH)D levels, including dietary vitamin D intake, ancestry, skin pigmentation and UVR exposure. Results: There were no significant baseline differences between cases and controls for serum 25(OH)D levels, dietary vitamin D and daily servings of dairy products. Baseline differences were found for age (p&amp;lt;.001), alcohol intake (p&amp;lt;.001) and supplemental vitamin D (p=.004). Multiple logistic regression analysis found no association with serum 25(OH)D levels and PCa risk. Preliminary analysis revealed that supplemental vitamin D (p=.004) and UVR exposure (p=0.03) were determinants of serum 25(OH)D level. Also, there were potential interactions between skin color, dietary vitamin D, serum 25(OH)D levels and risk for PCa. Conclusion: Supplemental vitamin D and UVR exposure were modifiers of serum 25(OH)D levels. However, we did not observe any significant difference in serum 25(OH)D levels between AA PCa cases and controls. This is likely due to factors such as diet, skin color, BMI and UVR exposure which strongly could influence vitamin D levels and function. Understanding the role of vitamin D in PCa risk may help to explain the higher incidence of PCa among AA males. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A78.

Abstract PR-8: Gene-environment interactions between JAZF1 and occupational and neighborhood lead exposure in African American prostate cancer cases

Abstract African American men have the highest incidence of prostate cancer in the world and have substantially higher rates of prostate cancer when compared to white men in the U.S. The cause(s) for this race disparity remains elusive. A single nucleotide polymorphism (SNP), rs10486567, in intron 2 of juxtaposed with another zinc finger protein 1 (JAZF1) has been associated with increased risk of prostate cancer in genome-wide association studies (GWAS) and may be key to uncovering reasons for disparities in the disease. JAZF1 is a cysteine-hystidine structured zinc finger protein, a type of protein that has been shown to interact with lead in vitro. Lead is recognized as a probable carcinogen in humans and African American men who are residentially segregated to industrialized urban environments in the U.S. have higher blood lead levels on average compared to white men. In a case-only study of 228 African American men with prostate cancer diagnosed at a large health system in the Detroit Metropolitan area, we assessed gene-environment interactions (GxE) between rs10486567 (CC vs. CT/TT genotype) and two sources of lead exposure. Lifetime occupational lead exposure was determined through industrial hygiene review of extensive face-to-face interviews. Neighborhood lead exposure, defined as the median proportion of census tract housing built before 1950 (≥ 47% vs. &amp;lt;47%), was derived from subjects address at time of diagnosis. Generalized estimating equation (GEE) modeling was used for analyses that included nested census data. In younger African American cases (&amp;lt;62 years of age), we found a significant gene-environment interaction between rs10486567 CC carriers and high occupational-respiratory lead exposure when compared to those with no respiratory lead exposure (OR 2.68, CI 1.05-6.88, p=.04). A significant GxE interaction was also observed between CC carriers and residence in a neighborhood with a large proportion of older housing in all cases and younger cases (all OR 1.92, CI 1.12-3.29, p=.017, younger OR 2.64, CI 1.21-5.73, p=.014, older OR 1.64, CI 0.73-3.70, p=.23). The interaction between rs10486567 and housing remained significant even after adjustment for occupational lead exposure. Combining lead exposure from occupation and neighborhood housing into a four category index showed even stronger interactions between the polymorphism and the highest lead exposed group compared to the lowest exposure group (all OR 3.13, CI 1.22-7.99, p=.017). These findings indicate that lead may be an important risk factor for prostate cancer in carriers of the rs10486567 CC genotype. Future studies of race disparities in prostate cancer should further assess interactions between lead and JAZF1 and lead and other zinc containing proteins. Focusing on genes and polymorphisms identified in GWAS studies might help to identify environmental risk factors for prostate cancer. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):PR-8.

Genetic variation in adiponectin (ADIPOQ) and the type 1 receptor (ADIPOR1), obesity and prostate cancer in African Americans

BackgroundAdiponectin is a protein derived from adipose tissue suspected to play an important role in prostate carcinogenesis. Variants in the adiponectin gene (ADIPOQ) and its type I receptor (ADIPOR1) have been recently linked to risk of both breast and colorectal cancer. Therefore, we set out to examine the relationship between polymorphisms in these genes, obesity and prostate cancer in study of African American men.MethodsTen single nucleotide polymorphisms (SNPs) in ADIPOQ and ADIPOR1 were genotyped in DNA samples from 131 African American prostate cancer cases and 344 controls participating in the Flint Men's Health Study. Logistic regression was then used to estimate their association with prostate cancer and obesity.ResultsWhile no significant associations were detected between any of the tested SNPs and prostate cancer, the rs1501299 SNP in ADIPOQ was significantly associated with body mass (p=0.03).ConclusionsGenetic variation in ADIPOQ and ADIPOR1 did not predict risk of prostate cancer in this study of African American men. However, the rs1501299 SNP in ADIPOQ was associated with obesity. Further investigation is warranted to determine if racial differences exist in the influence of the adiponectin pathway on prostate cancer risk.

Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor

Background: Prospective epidemiologic studies indicate that the risk for advanced prostate cancer is increased among men with high levels of serum calcium. Because serum calcium levels are influenced by the calcium-sensing receptor (CaSR), we examined prostate cancer in African American men in relation to three single nucleotide polymorphisms (SNPs) in the CaSR gene, A986S, R990G, and Q1011E. This is the first study of CaSR polymorphisms and risk of prostate cancerMethods: We genotyped three CaSR SNPs for 458 African American prostate cancer cases and 248 controls from a population-based case-control study, the California Collaborative Prostate Cancer Study.Results: The CaSR genotypes were not associated with prostate cancer overall. However, we observed significant heterogeneity by disease stage for the Q1011E polymorphism (p=0.02). Advanced cases were significantly less likely than controls or localized cases to be homozygous for the minor allele of the Q1011E polymorphism (1% vs. 5%). Cases with advanced disease were six times less likely to carry two copies of the minor allele than were controls (OR=0.16, p=0.02) or localized cases (OR=0.15, p=0.01) and were significantly older at diagnosis (68.8 ±5.7 vs. 64.0 ± 9.0 years for the QQ and EE genotypes, p = 0.004).Conclusions: The CaSR Q1011E minor allele, which is common in populations with African ancestry, may be associated with a less aggressive form of prostate cancer among African American men.

NAT2 and NER genetic variants and sporadic prostate cancer susceptibility in African Americans

Prostate cancer is a common malignancy that disproportionately affects African-American men. Environmental factors and variation in genes responsible for chemical and dietary carcinogen metabolism and DNA damage repair may modulate risk. Fourteen single nucleotide polymorphisms in NAT2 and four NER genes (ERCC1, XPF/ERCC4, XPG/ERCC5 and CSB/ERCC6) were genotyped in a case-control study of 254 African-American prostate cancer cases and 301 healthy controls from Washington, DC. Smoking status, BMI, age and genetic ancestry were included as covariates in the association analyses. We found that individuals homozygous for the XPG/ERCC5 -72C/T promoter polymorphism had a significant reduction in risk, for prostate cancer (OR=0.12; 95% CI=0.03-0.48). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P=0.003). In silica analyses suggest a functional implication for the promoter variant since it deletes a GCF transcriptional factor-binding site responsible for the downregulation of transcription. The protective effect of the promoter SNP on risk for prostate cancer was independent of smoking. In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk. Additional tests for genotype interactions were not significant. We note that there may be other factors, such as dietary exposures, which may modulate prostate cancer risk in combination with genetic variation within the NAT2 and NER genes. Our results, in combination with previous observations of LOH for ERCC5 in prostate tumors, provide further evidence for a role of XPG/ERCC5 in the etiology of prostate cancer.