Barashi Nimrod S, Li Tiandao, Angappulige Duminduni H, Zhang Bo, O'Gorman Harry, Nottingham Charles U, Shetty Anup S, Ippolito Joseph E, Andriole Gerald L, Mahajan Nupam P, Kim Eric H, Mahajan Kiran
Division of Urologic Surgery, Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA.
Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, USA.
Cancers (Basel). 2024 Jan 2;16(1):213. doi: 10.3390/cancers16010213.
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.
我们的目标是识别基因表达的变化，这些变化有助于阐明良性前列腺增生（BPH）男性患前列腺癌（PCa）的发展途径。我们纳入了98名患有BPH、前列腺MRI检查结果为阳性（前列腺影像报告和数据系统；PIRADS≥4）且活检结果为阴性的男性，研究时间为2014年11月至2018年1月。对来自MRI病变部位和一个地理上较远区域（每位患者两个区域）的组织芯进行了RNA测序（RNA-Seq）。对所有患者进行了至少三年的随访，以确定哪些人后来发展为PCa。我们比较了未发展为PCa的患者（“仅BPH”）与发展为PCa的患者（“BPH/PCa”）的基因表达。然后，我们确定了美国泌尿外科学会（AUA）症状评分最高的BPH男性子集（“有症状的BPH”），并将他们的基因表达与BPH/PCa组进行比较。在中位随访47.5个月时，15名男性发展为PCa，而83名未发展。我们比较了14名有症状的BPH男性（AUA评分≥18）与15名BPH/PCa男性的基因表达。我们发现了两组基因，表明这两组具有独特的分子特征。差异分析揭示了在仅BPH中上调而在BPH/PCa中下调的基因，反之亦然。有症状的BPH男性的T细胞活化标志物（TCR、CD3、ZAP70、IL-2和IFN-γ以及趋化因子受体CXCL9/10）表达上调。相比之下，BPH/PCa男性中与管腔上皮祖细胞相关的NKX3-1和HOXB13转录因子上调，但免疫细胞减少，这表明在免疫逃逸中存在细胞自主作用。具有免疫丰富景观的有症状BPH可能支持抗肿瘤免疫。良性前列腺活检组织的RNA测序显示NKX3-1和HOXB13上调且无T细胞，这可能有助于识别未来发生PCa风险较高的男性，这对于确定正在进行的PCa筛查可能有用。
