Zhang Peng, Chen Tieding, Yang Ming
Department of Urology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, China.
PLoS One. 2025 Apr 15;20(4):e0321728. doi: 10.1371/journal.pone.0321728. eCollection 2025.
Prostate cancer (PCa) patients with low prostate-specific antigen (PSA) levels can occasionally present high-grade disease. These patients often exhibit resistance to androgen deprivation therapy and have poor outcomes. The mechanisms underlying these observations remain poorly understood. This study aimed to investigate the clinical characteristics and potential gene expression mechanisms in this subgroup.
Clinical data from 365,558 PCa patients were categorized into four groups based on PSA levels and Gleason score (GS): Group 1 (PSA ≤ 2.5 ng/mL, GS < 8), Group 2 (PSA ≤ 2.5 ng/mL, GS ≥ 8), Group 3 (PSA > 2.5 ng/mL, GS < 8), and Group 4 (PSA > 2.5 ng/mL, GS ≥ 8). Clinical characteristics were compared using Kruskal-Wallis H and Pearson's chi-squared tests. Competing-risks regression assessed prostate cancer-specific mortality (PCSM). Gene set enrichment analysis (GSEA) was performed on 219 PCa patients to compare Group A (PSA ≤ 2.5 ng/mL, GS ≥ 8) with Group B (PSA > 2.5 ng/mL, GS ≥ 8).
Group 2 had a significantly higher tumor stage (p < 0.001) and increased hazard ratio for PCSM (p < 0.001). GSEA in Group A identified 156 upregulated gene sets and highlighted several enriched pathways, including the polycomb repressive complex 2, the epidermal growth factor receptor family, retrograde axonal transport, the tumor necrosis factor/nuclear factor-κB pathway, the Rho guanine nucleotide exchange factor/RhoA pathway, and the phosphoinositide 3-kinase signaling pathways (p < 0.05, false discovery rate-adjusted p < 0.25).
PCa patients with low PSA levels and high GS demonstrated an increased risk of PCSM. They were characterized by the aberrant activation of multiple signaling pathways. Targeted therapeutic strategies aimed at these pathways warrant further investigation for their potential to improve outcomes in this aggressive PCa subtype.
前列腺特异性抗原（PSA）水平较低的前列腺癌（PCa）患者偶尔会出现高级别疾病。这些患者通常对雄激素剥夺疗法耐药，预后较差。这些观察结果背后的机制仍知之甚少。本研究旨在调查该亚组患者的临床特征和潜在的基因表达机制。
365558例PCa患者的临床数据根据PSA水平和 Gleason评分（GS）分为四组：第1组（PSA≤2.5 ng/mL，GS<8）、第2组（PSA≤2.5 ng/mL，GS≥8）、第3组（PSA>2.5 ng/mL，GS<8）和第4组（PSA>2.5 ng/mL，GS≥8）。使用Kruskal-Wallis H检验和Pearson卡方检验比较临床特征。竞争风险回归评估前列腺癌特异性死亡率（PCSM）。对219例PCa患者进行基因集富集分析（GSEA），以比较A组（PSA≤2.5 ng/mL，GS≥8）和B组（PSA>2.5 ng/mL，GS≥8）。
第2组的肿瘤分期显著更高（p<0.001），PCSM的风险比增加（p<0.001）。A组的GSEA鉴定出156个上调的基因集，并突出了几个富集的通路，包括多梳抑制复合物2、表皮生长因子受体家族、逆行轴突运输、肿瘤坏死因子/核因子-κB通路 Rho鸟嘌呤核苷酸交换因子/RhoA通路和磷脂酰肌醇3激酶信号通路（p<0.05，错误发现率调整后p<0.25）。
PSA水平低且GS高的PCa患者显示出PCSM风险增加。其特征是多种信号通路异常激活。针对这些通路的靶向治疗策略有望进一步研究，以探讨其改善这种侵袭性PCa亚型预后的潜力。
