Prostate cancer (PCa) of African Americans (AA) is diagnosed at an earlier median age and more advanced stage than PCa of European American (EA), and has a poorer prognosis and significantly higher mortality. 35% of AA PCa patients fall out of active surveillance, compared to 15% of EA men. Stromal cells adjacent to tumor, including reactive stroma, play a critical role in tumorigenesis of prostate cancer. We searched for differences in RNA expression in the stroma and tumor of AA compared to EA prostate cancer patients to uncover regulatory differences that might contribute to a higher rate of aggressive PCa in AA men.
RNA-Seq data was generated for tumor-adjacent stroma of prostate cancer FFPE tissues from 9 AA and 8 EA patients. RNA-Seq of tumor epithelium from 22 AA and 46 EA PCa FFPE tissues was obtained from GEO database accession GSE54460. Samples were matched clinically for Gleason score, age, and relapse status. Geographic origin was determined using the program Locating Ancestry from Sequencing Reads (LASER) which provides the fraction of ancestry based on single nucleotide polymorphisms (SNPs).The program CIBERSORT, which is an estimate of fraction of immune cells in tissues, was used to estimate the relative fractions of 22 immune cell types in each RNA-Seq sample. Pathway analysis was performed using Strand-NGS and Ingenuity Pathway Analysis (IPA) tools.
PCa-adjacent stroma from 9 AA were compared to 8 EA. Similarly, tumor tissues from 22 AA were compared to 46 EA. Comparisons of AA and EA tumor-adjacent stroma identified 721 downregulated and 790 upregulated genes in AA, using a corrected p value of < 0.05. We found significant association of downregulated genes in AA tumor stroma with immune response pathways. Among upregulated genes in AA relative to EA, several metabolic pathways, signaling by TGF beta receptor complex, cytokine, and inflammatory responses, were significantly enriched.
CIBERSORT analysis, revealed M2 macrophages (i.e. immunosuppressive and proangiogenic macrophages were enriched in both AA and EA tumor stroma, and represented 25% and 27% of screened immune cells, respectively. The frequency of activated DCs in tumor-adjacent stroma of EA was 7-fold higher than in tumor stroma of AA patients (21% vs 3%).
22 AA and 46 EA prostate tumor tissue samples were similarly compared. 425 upregulated and 514 downregulated genes were identified (corrected p value of 0.05). Although, stroma and tumor have very different transcription patterns, there were 17 genes up-regulated both in tumor-adjacent stroma and tumor epithelium of AA compared to EA and these were enriched in the IL-6 signaling pathway. 21 down-regulated genes were enriched in miRNA targeted genes.
In contrast, to tumor-adjacent stroma, immune response pathways in tumor of AA compared to EA was different, suggesting a distinct immune response in tumor-adjacent stroma compared to tumor in men of different races.
Citation Format: Farah Rahmatpanah, Gabriela De Robles, Dan Mercola, Michael Lilly, Michael McClelland. RNA expression differences between African Americans and European Americans prostate cancers in both their tumor-adjacent stroma and in their tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1558.