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African American (AA) men have an approximately 60% higher incidence of prostate cancer (PCa) and have about two times greater risk of dying of the disease than their European American (EA) counterparts. Despite this staggeringly unequal burden of PCa incidence and outcome between AA and EA men, there is limited insight into the molecular mechanisms associated with this racial disparity. Using state-of-the-art mass spectrometry platform, we uncovered the very first metabolic and lipidomics landscape in PCa/benign adjacent tissue pairs and paired plasma and urine containing epidemiologic meta-data from ancestry-typed AA and EA men. A total of 190 polar and mid-polar metabolites and 495 lipids were measured in tissues and 183 metabolites and lipids were examined in the plasma and urine samples. AA PCa tissue and plasma signatures had unique alterations in metabolites and key enzymes associated with the methionine-homocysteine pathway, including adenosine and inosine levels, compared to corresponding tissues and plasma from EA case controls and EA PCa tissues. Intriguingly, methionine levels in AA PCa were also portrayed by distinct dietary practices in these patients. In addition, AA PCa tissues demonstrated unique patterns of bioenergetic metabolites and accumulated lipids reflecting impaired mitochondrial activity and TCA cycle. Further characterization of these first-in-the-field findings demonstrating reprogrammed metabolism in AA PCa relative to EA tumors could reveal insights into the biologic basis of PCa disparities and novel areas for therapeutic intervention. Citation Format: Stacy M. Lloyd*, Jie H. Gohlke*, Sumanta Basu*, Vasanta Putluri,Shaiju K Vareed, Rebeca San Martin, Thekkelnaycke Rajendiran, Tiffany A. Dorsey, Bandana Prasad, Rajni Sonavane, Uttam Rasaily, James Henderson, Balasubramanyam Karanam, Harene Venghatakrishnan, Salil Bhowmik, Alexander Zaslavsky,Nilanjan Guha, Rick Kittles, Stefan Ambs, Michael Ittmann,David Rowley, Ganesh Palapattu, Nagireddy Putluri,George Michailidis, Arun Sreekumar. Metabolomic landscape of African American prostate cancer: Insights into the biologic basis of the racial disparity [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 B92.

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.

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. However, when these factors are statistically controlled, the differences in incidence, morbidity, and mortality between AA and EA PCa persist. These findings support the notion that biological factors are one of the major driving forces of PCa disparities. 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 and the associated bioprocesses, may contribute to PCa health disparities 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. 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. Results: Unique biochemical alterations associated with AA tumors were identified. Pathways such as cysteine/methionine, arginine/proline and de novo purine biosynthesis were enhanced in AA PCa. Metabolites such as cystathione, cysteine, and S-Adenosylhomocysteine (SAH), are elevated in AA PCa compared to matched adjacent benign. Consistent with this, transcript and protein levels of DNA Methyl Transferase 1 (DNMT1) and Cystathione Beta Synthase (CBS) were elevated in AA PCa tissues and cell lines. Interestingly, protein and transcript levels of Adenosine Deaminase, an enzyme that converts SAM-derived adenosine to inosine was significantly down regulated in AA PCa, both in tissues and cell lines. Consistent with this, accumulated levels of adenosine were found in AA PCa. Conclusions: Taken together, the metabolomics data alludes to the existence of an efficient immune escape mechanism in AA PCa. Corroborating this, analysis of gene expression data from AA men with PCa also reveals enriched immune escape pathways. Citation Format: Stacy M. Lloyd, Jie Gohlke, Sumanta Basu, Salil Bhowmik, Vasanta Putluri, Rashmi Krishnapurnam, Kimal Rajapakshe, Cristian Coarfa, Nilanjan Guha, SA Deepak, Arunkumar Padmanabhan, Mohammed Sayeeduddin, Patricia Castro, 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 Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A65.