Abstract C092: Transcriptome analysis of human endogenous retroviral elements in tumor microenvironment of prostate cancer patients of different ancestry
Authors: Jennings Tara S. K. , Kumar Vinay , Nguyen Anton N. , Ittmann Michael M. , Castro Patricia , Rahmatpanah Farah 
Published: September 2024

Background: Prostate cancer (PCa) poses unique challenges for Non-Hispanic Black Americans (BA), who often face poorer outcomes than Non-Hispanic White Americans (WA). Even after adjusting for socioeconomic factors, BAs are diagnosed younger and experience more severe clinical effects, potentially due to the tumor microenvironment. Within PCa, Endogenous Retroviruses (ERVs) have been shown to regulate immune response genes and have prognostic value in PCa. Despite constituting 8% of the human, ERVs' role in the tumor microenvironment remains incompletely understood. These findings highlight the need to target microenvironment dysregulation in solid tumor therapies, especially for ERV expression in prostate cancer. Methods: Using RNA-sequencing, we investigated the expression of ERVs in BA (n=18) and WA (n=14) tumor adjacent stroma (TAS) samples. We analyzed reads by mapping them to the human genome (hg38). We then used bedtools and data from the Human Endogenous Retrovirus database (HERVd) to calculate the number of reads at each ERV locus (n=519,060). Differentially expressed ERV elements were then identified in an Audic Claverie Test (fold- change cutoff of 2 and padj &lt; 0.05). The expression of protein-coding genes in the same BA (n=18) and WA (n=14) TAS samples was investigated using RNA-sequencing. Regulation of significant ERV elements were compared to the regulation of nearby immune response genes between the two races. We developed primary stroma (carcinoma associated fibroblast, CAFs) culture of different races with PCa using fresh prostatectomy tissues. To investigate the biological functions of ERVs in CAFs, we developed FANA oligonucleotides (synthetic single- stranded nucleic acid analogs that can modulate gene expression by enzymatic degradation of a target RNA) and corresponding primers to knock down specific ERV sequences near key immune response genes in prostate cancer. Results: We examined 32 prostatectomy specimens of BA (n=18) and WA (n=14) PCa. Of the 5,786 statistically significant differentially expressed ERV elements between BA and WA TAS that were identified, 3,274 elements had an increase in ERV expression for BA TAS, and 2,512 elements had a decrease in ERV expression for BA TAS. 61 MER41 elements were found to be differentially expressed between the two races. The MER family sequences contain binding sites for transcription factors that are crucial in cancer, such as STAT1. This transcription factor can regulate genes involved in cell proliferation, apoptosis, and DNA repair. MER41 is in close proximity (within 5000 base pairs) to IFNA6, an immune response gene. We found both MER41 and IFNA6 to be downregulated in BA TAS, as compared to their WA counterparts. We developed FANA oligonucleotides to knockdown MER41E, MER61-Int, HERVL-Int, MLT1A, and LTR61E1 to investigate their effect on nearby gene expression. Conclusion: The CAF models from PCa patients of different races can be used to explore the biological function of ERV inactivation on anti-tumor immune response genes within the tumor microenvironment.

Citation Format: Tara S. K. Jennings, Vinay Kumar, Anton N. Nguyen, Michael M. Ittmann, Patricia Castro, Farah Rahmatpanah. Transcriptome analysis of human endogenous retroviral elements in tumor microenvironment of prostate cancer patients of different ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C092.