Abstract 5133: Identification of distinct gene expression profiles in African Americans and Caucasian men with prostate cancer
Authors: Mori Joakin , Williams Raven , Lin Hui-Xian , Becks Alahni , White Jason , Karanam Balasubramanyam , Yates Clayton , Wang Honghe 
Published: August 2019

Introduction African Americans (AA) are disproportionately affected by prostate cancer (PCa) compared to European Americans (EA). Genetic and epigenetic differences have been implicated in this racial disparity. Present PCa diagnostic and treatment regimens have focused mainly on gene fusion product involving the androgen driven transmembrane protease serine 2 (TMPRSS2) and the transcription factor, ETS related gene (ERG). However, TMPRSS2:ERG (T2E) fusion product is common mainly to EA (50-80% of patients) and has lower prevalence amongst other ethnicities including AAs (10-30%), Japanese and Chinese patients. In addition, T2E negative PCa subtype has been associated with increased risk of developing castration resistant PCa (CRPC). This study aims at classifying PCa by molecular and pathologic subtypes that drive disease aggressiveness in patients of AA and EA ancestry.

Methodology Prostate cancer tissue slides obtained from EA and AA patients were stained for ERG expression. Laser-capture micro-dissected RNAs from formalin-fixed paraffin-embedded tissues were used for RNA-seq. DESeq2 was used as a statistical procedure to call differentially expressed genes (DEGs) in different samples. Data set from Powell was also analyzed for DEGs between ERG positive and ERG negative samples. Leading-Edge Analysis (GSEA v2.2.4) was performed to determine the representation of DEGs across enriched gene sets.

Results 32.4% of EA were ERG positive compared to 29% of AA that stained positive. More EA samples (26.4%) had high intensity staining (2≥ on a 1 - 3 scale) compared to AA samples (25.8%). Over 11% of EA samples had high (4) distribution of ERG positive staining compared 6.5% in AA samples. Analysis of the Powell dataset (GSE41696) revealed 301 DEGs and gene set enrichment analysis identified immune system process, regulation of cellular component and homeostatic process as most biological processes affected by DEGs. Other processes significantly affected included: cell motility, cell activation and regulation of locomotion. At least 15 genes including: CCL5, TLR4, PIK3CB, CD86, KIT, CD40, ITGB3, PDGFRA, LEF1, HIF1A, CLU, PLA2G6, GLI3, PIK3CA and TNNB1, were present in at least 10 enriched gene sets. The DEGs across enriched gene sets showed gene signatures involved in Wnt signaling, PI3K, chemokines and receptor tyrosine kinases.

Conclusion Specific sets of genes are differentially enriched between EGR-/AR- and ERG+/AR+. These findings suggest that PCas have a distinct gene expression profile in the absence of the T2E fusion, which may act as a driver of disease aggressiveness and racial health disparities in PCa. Identifying these differences in gene-signature expression and signaling transduction pathways will allow stratification of men across races and identify, early on, those individuals who are likely to develop the most aggressive disease.

Citation Format: Joakin Mori, Raven Williams, Hui-Xian Lin, Alahni Becks, Jason White, Balasubramanyam Karanam, Clayton Yates, Honghe Wang. Identification of distinct gene expression profiles in African Americans and Caucasian men with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5133.