Symptomatic Benign Prostatic Hyperplasia with Suppressed Epigenetic Regulator HOXB13 Shows a Lower Incidence of Prostate Cancer Development

Simple Summary Patients with symptomatic Benign Prostatic Hyperplasia (BPH) showed upregulated gene expression of biological pathways associated with T cell activation and suppression of a key transcription factor HOXB13, which is associated with transcription and epigenetic regulation of prostate cancer (PCa). In contrast, patients with BPH who later developed PCa showed significantly reduced inflammation and revealed activation of several transcription factors related to PCa, including HOXB13, AR, FOXA1 and SIM2. It may be clinically beneficial for urologists to be able to distinguish between men with BPH who are at a higher risk of developing PCa in the future based on their molecular subtype.Abstract Our objective was to identify variations in gene expression that could help elucidate the pathways for the development of prostate cancer (PCa) in men with Benign Prostatic Hyperplasia (BPH). We included 98 men with BPH, a positive prostate MRI (Prostate Imaging Reporting and Data System; PIRADS >= 4), and a negative biopsy from November 2014 to January 2018. RNA sequencing (RNA-Seq) was performed on tissue cores from the MRI lesion and a geographically distant region (two regions per patient). All patients were followed for at least three years to identify who went on to develop PCa. We compared the gene expressions of those who did not develop PCa ("BPH-only") vs. those who did ("BPH/PCa"). Then, we identified the subset of men with BPH who had the highest American Urological Association (AUA) symptom scores ("symptomatic BPH") and compared their gene expression to the BPH/PCa group. At a median follow-up of 47.5 months, 15 men had developed PCa while 83 did not. We compared gene expressions of 14 men with symptomatic BPH (AUAss >= 18) vs. 15 with BPH/PCa. We found two clusters of genes, suggesting the two groups had distinctive molecular features. Differential analysis revealed genes that were upregulated in BPH-only and downregulated in BPH/PCa, and vice versa. Symptomatic BPH men had upregulation of T-cell activation markers (TCR, CD3, ZAP70, IL-2 and IFN-gamma and chemokine receptors, CXCL9/10) expression. In contrast, men with BPH/PCa had upregulation of NKX3-1 and HOXB13 transcription factors associated with luminal epithelial progenitors but depleted of immune cells, suggesting a cell-autonomous role in immune evasion. Symptomatic BPH with immune-enriched landscapes may support anti-tumor immunity. RNA sequencing of benign prostate biopsy tissue showing upregulation of NKX3-1 and HOXB13 with the absence of T-cells might help in identifying men at higher risk of future PCa development, which may be useful in determining ongoing PCa screening.