Abstract 3675: Epigenetic variations associated with therapy resistance among prostate tumors from Puerto Rican men
Authors: Osterman Carlos J. Diaz , Berglund Anders , Martinez Shannalee , Luis Camila , Dutil Julie , Matta Jaime , Encarnacion-Medina Jarline , Ortiz-Sanchéz Carmen , Wang Liang , Dhillon Jasreman , Kim Youngchul , Park Hyun Y. , Ruiz-Deya Gilbert , Yamoah Kosj , Park Jong Y. 
Published: June 2022

Prostate cancer (PCa) is the leading cause of cancer-related death in Puerto Rican (PR) men, a population at higher risk of developing the disease than other Hispanic/Latino groups. But the relationship between this phenomenon and epigenetics, and how this relationship explains PCa racial and ethnic health disparities are controversial. The purpose of this study was to expand on the knowledge regarding epigenetic differences in terms of DNA methylation to enable risk stratification and treatment selection in this genetically admixed population. In addition, we aim to assess differential DNA methylation patterns associated with drug resistance in PCa in PR Hispanic/Latino men. Since epigenetic changes and modifications represent critical components of carcinogenesis and progression, we are expecting differential methylation levels between aggressive vs. indolent, and resistant vs. non-resistant cases. Prostate tumors from PR men were stratified based on Gleason score. Methylation levels were measured by Illumina Infinium Methylation EPIC BeadChip DNA methylation platform, and bioinformatic analyses. In parallel, DNA methylation profiles were also analyzed using genomic DNA from PCa cells selected for resistance to androgen depletion, enzalutamide resistance, or docetaxel resistance. We identified 1,225 differentially methylated genes in prostate tumors compared with normal adjacent tissues, and 141 differentially methylated genes between aggressive vs. indolent tumors. Additionally, 723 differentially methylated genes were found in therapy resistant cell lines compared to parental controls. Analysis of the methylated genes obtained from aggressive prostate tumors from Puerto Rican patients and therapy-resistant PCa cell lines revealed four overlapping methylated genes: RNF220, FAM65B, PRDM16, and DGKH. Further analysis of PCa cells resistant to androgen depletion, enzalutamide, or docetaxel demonstrated impaired cellular migration of resistant phenotypes upon DNA methyltransferase (DNMT) inhibition using 5-azacytidine or zebularine compared to parental cell lines. DNMT1 was associated with resistance in PCa cell lines, and future studies will include silencing of methyltransferases will evaluation of drug re-sensitization. These findings provide critical insight into the epigenetic landscape of aggressive prostate tumors among PR men and highlight several candidate methylation biomarkers for assessing risk in this population.

Citation Format: Carlos J. Diaz Osterman, Anders Berglund, Shannalee Martinez, Camila Luis, Julie Dutil, Jaime Matta, Jarline Encarnacion-Medina, Carmen Ortiz-Sanchéz, Liang Wang, Jasreman Dhillon, Youngchul Kim, Hyun Y. Park, Gilbert Ruiz-Deya, Kosj Yamoah, Jong Y. Park. Epigenetic variations associated with therapy resistance among prostate tumors from Puerto Rican men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3675.