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-γ 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.
本研究旨在识别基因表达差异，以阐明良性前列腺增生（BPH）患者发展为前列腺癌（PCa）的潜在通路。我们纳入了2014年11月至2018年1月期间98例经前列腺磁共振成像（采用前列腺影像报告和数据系统；PIRADS评分≥4）提示可疑病灶但穿刺活检结果为阴性的BPH患者。对每位患者MRI可疑病灶区域及远离该病灶区域（每位患者取两个区域）的组织样本进行RNA测序。所有患者均接受至少三年随访，以确定后续发展为PCa的病例。我们比较了未发展为PCa者（“单纯BPH组”）与最终发展为PCa者（“BPH/PCa组”）的基因表达差异。随后，我们筛选出美国泌尿外科协会（AUA）症状评分最高的BPH亚组（“症状性BPH组”），并将其基因表达与BPH/PCa组进行对比。 中位随访47.5个月后，15例患者发展为PCa，83例未发生癌变。我们比较了14例症状性BPH患者（AUA症状评分≥18）与15例BPH/PCa患者的基因表达谱，发现两组存在显著差异的基因簇，提示其具有不同的分子特征。差异表达分析显示部分基因在单纯BPH组中上调而在BPH/PCa组中下调，另一些基因则呈现相反趋势。症状性BPH患者表现出T细胞活化标志物（TCR、CD3、ZAP70、IL-2和IFN-γ）及趋化因子受体（CXCL9/10）表达上调。与之相反，BPH/PCa患者则出现与管腔上皮祖细胞相关的转录因子NKX3-1和HOXB13上调，同时伴随免疫细胞缺失，提示其通过细胞自主机制实现免疫逃逸。具有免疫富集微环境的症状性BPH可能支持抗肿瘤免疫。对良性前列腺活检组织的RNA测序显示，NKX3-1和HOXB13上调伴随T细胞缺失的特征，可能有助于识别未来PCa高风险人群，这对制定个体化前列腺癌筛查策略具有重要参考价值。
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