Abstract PR10: An Integromics Approach Identifies Immune Escape as a Potential Mechanism for Prostate Cancer Disparities

Abstract

Background: AA men with PCa will die at a rate nearly 2.5 times higher than their EA counterparts. Presently, no mechanism has been described to explain the differences observed between AA and EA men with PCa; yet, many have interrogated the role of social and anthropometric data on PCa outcomes within these populations. Therefore, to obtain better insights into the molecular aspects of PCa disparities, we examined metabolomic and gene expression profiles of PCa and matched adjacent benign tissue from AA and EA men. Metabolomics is defined as the study of all the small molecule metabolites produced by cellular processes in the body. We hypothesize that racially distinct metabolic pathways may contribute to PCa health disparities and also delineate mechanistic biological pathways. Methodology: A total of 190 polar and mid-polar metabolites were measured using mass spectrometry across 50 and 28 PCa/benign tissue pairs from AA and EA men, respectively. Likewise, gene expression microarray analysis was performed on 48 and 21 PCa/benign tissue pairs from AA and EA men, and gene set enrichment (GSEA) analysis was performed. Ancestry informative markers were genotyped and ancestry estimates were determined. Metabolic profiles of AA and EA PCa and benign adjacent pairs were compared using paired t-tests. FDR corrected p-values were used to detect differential metabolites and genes. Biological validation was performed using tissue microarrays, qPCR, and western blots. Results: Unique biochemical alterations associated with AA tumors were identified. Relative to EA tumors, AA tumors had significant alterations in the cysteine/methionine pathway; specifically accumulations of adenosine were most prominent in AA PCa, as well as urine. Protein and transcript levels of Adenosine Deaminase (ADA), an enzyme that converts SAM-derived adenosine to inosine was significantly down regulated in AA PCa, a finding validated in both tissue and cell lines. GSEA analysis revealed that genes involved in the immune system were prominent among AA PCa compared to EA PCa. To this end, significant inverse correlations between ADA and CD4+, CD8+, and CD68+ levels were also identified. Conclusions: Taken together, this integromics approach generated data that alludes to the existence of an efficient immune escape mechanism in AA PCa, which may explain the disparity facing AA men with PCa. Citation Format: Stacy M. Lloyd, Jie Gohlke, Sumanta Basu, Salil Bhowmik, Vasanta Putluri, Kimal Rajapakshe, Cristian Coarfa, Michael Ittmann, Ganesh Palapattu, Nagireddy Putluri, George Michailidis, Arun Sreekumar. An Integromics Approach Identifies Immune Escape as a Potential Mechanism for Prostate Cancer Disparities. [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 PR10.