Abstract PO-136: Major signaling pathways associated with biochemical recurrence in Hispanic/Latino patients with prostate cancer

Abstract

Abstract Purpose. A high number of diagnosed prostate cancer (PCa) tumors are indolent and will never become aggressive during a patient's lifetime, however, about 20%-40% will experience post-operative disease relapse with biochemical recurrence (BCR), and a fraction of these will progress towards metastatic disease, which is the leading cause of PCa death. Reliable biomarkers helping in management decision-making and avoiding resistant PCa are still needed. We aimed to identify differentially expressed genes (DEGs) associated with BCR in localized PCa and to explore their involvement in signaling pathways contributing to the progression of PCa in Hispanic/Latino patients. Methods. A total of 117 Hispanic/Latino cases with localized PCa were included. RNA was extracted from FFPE tissues of radical prostatectomy (RP), RNA-seq was performed in 75 cases and used to identify DEGs between BCR positive (BCR) and BCR negative (non-BCR) cases. Signaling pathway analysis was done in MetaCore and DAVID database. DEGs with a p-value < 0.1 were used for enrichment analysis. Results. We identified 21 DEGs between BCR and non-BCR cases, three upregulated and 19 downregulated. From the enriched pathway maps found through MetaCore, the most remarkable pathways related with BCR included metabolism of androgen hormones; differentiation, self-renewal and maintenance of stem cells; mechanisms operating in type 2 diabetes (T2DM) and the cooperative action by pioglitazone and rosiglitazone with metformin; and metabolism of triacylglycerol. In line with these findings, results from DAVID also found Diabetes mellitus as one of the keywords, with downregulation of adiponectin (ADIPOQ) and MCF2L2 as the main genes related to this pathway. Other studies have shown that, regardless of BMI, individuals with T2DM have lower plasma adiponectin levels, which, in turn, are associated with pathophysiological conditions such as obesity, metabolic syndrome and insulin resistance. In our study, BMI was not associated with BCR, however, other complementary measurements related to increased abdominal fat (e.g., waist circumference or waist-to-hip ratio), and with recent evidence of strong association with aggressive PCa, were not assessed by us. Additional pathways associated with BCR progression were those related to biosynthesis and metabolism of androgens, being AKR1C the main gene involved. This gene participates in alternative pathways of the biosynthesis of androgens; for example, downregulated AKR1C leads to the synthesis of dihydrotestosterone and circumvents testosterone as a precursor. Conclusions. Enrichment analyses suggest that pathways related to T2DM and metabolism of androgens are main drivers of BCR in Hispanic/Latino PCa patients, mainly through the downregulation of ADIPOQ and AKR1C. Our findings confirm recent discoveries in the molecular understanding of PCa progression, but more studies analyzing abdominal fat measures in independent and larger cohorts could lead as to more precise conclusions, as well as to identify potential biomarkers and therapeutic targets. Citation Format: Natalia L. Acosta-Vega, Rodolfo Varela, Jorge Andrés Mesa, Jone Garay, Melody C. Baddoo, Alberto Gómez-Gutiérrez, Silvia J. Serrano-Gómez, Martha Lucía Serrano, Jovanny Zabaleta, Alba L. Combita, María Carolina Sanabria-Salas. Major signaling pathways associated with biochemical recurrence in Hispanic/Latino patients with prostate cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-136.