Rounbehler, Robert J.

Abstract Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial–mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21–4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52–3.86; P = 0.0001) but not in EAM. Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

AbstractBackground: We studied the utility of the tumor suppressor Tristetraprolin (TTP, ZFP36) as a clinically relevant biomarker of aggressive disease in prostate cancer patients after radical prostatectomy (RP).Methods: TTP RNA expression was measured in an RP cohort of patients treated at Moffitt Cancer Center (MCC) and obtained from six publically available RP datasets with biochemical recurrence (BCR; total n = 1,394) and/or metastatic outcome data (total n = 1,222). TTP protein expression was measured by immunohistochemistry in a tissue microarray of 153 MCC RP samples. The time to BCR or metastasis based on TTP RNA or protein levels was calculated using the Kaplan–Meier analysis. Univariable and multivariable Cox proportional hazard models were performed on multiple cohorts to evaluate if TTP is a clinically relevant biomarker and to assess if TTP improves upon the Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score for predicting clinical outcomes.Results: In all of the RP patient cohorts, prostate cancer with low TTP RNA or protein levels had decreased time to BCR or metastasis versus TTP-high tumors. Further, the decreased time to BCR in TTP-low prostate cancer was more pronounced in low-grade tumors. Finally, pooled survival analysis suggests that TTP RNA expression provides independent information beyond CAPRA-S to predict BCR.Conclusions: TTP is a promising prostate cancer biomarker for predicting which RP patients will have poor outcomes, especially for low-grade prostate cancer patients.Impact: This study suggests that TTP RNA expression can be used to enhance the accuracy of CAPRA-S to predict outcomes in patients treated with RP. Cancer Epidemiol Biomarkers Prev; 27(11); 1376–83. ©2018 AACR.