Integrative exploration of the mutual gene signatures and immune microenvironment between benign prostate hyperplasia and castration-resistant prostate cancer

Benign prostate hyperplasia (BPH) and prostate cancer (CaP) are among the most frequently occurring prostatic diseases. When CaP progressed to castration-resistant CaP (CRPC), the prognosis is poor. Although CaP/CRPC and BPH frequently coexist in prostate, the inter-relational mechanism between them is largely unknown. Single-cell RNA sequencing, bulk-RNA sequencing, and microarray data of BPH, CaP in the Gene Expression Omnibus database were obtained and comprehensively analyzed. Weighted Gene Co-Expression Network Analysis (WGCNA) and lasso regression analysis were performed to explore the potential biomarkers. With WGCNA, five modules in BPH, two in CaP, and three in CRPC were identified as significant modules. Pathway enrichment analysis found that the epigenetics and chromosomal-related signaling were dominantly clustered in the CaP group but not in BPH and CRPC. Lasso regression analysis was used to analyze further the mutual genes between the BPH module and the CRPC module. As a result, DDA1, ERG28, OGFOD1, and OXA1L were significantly correlated with the transcriptomic features in both BPH and CRPC. More importantly, the role of the four gene signatures was validated in two independent anti-PD-1 immunotherapy cohort. This study revealed the shared gene signatures and immune microenvironment between BPH and CRPC. The identified hub genes, including DDA1, ERG28, OGFOD1, and OXA1L, might be potential therapeutic targets for facilitating immunotherapy in prostate cancer.

良性前列腺增生（Benign prostate hyperplasia, BPH）与前列腺癌（prostate cancer, CaP）是临床最常见的前列腺疾病类型。当前列腺癌进展至去势抵抗性前列腺癌（castration-resistant CaP, CRPC）时，患者预后极差。尽管CaP/CRPC与BPH常共同存在于前列腺组织中，但二者间的相互作用机制目前尚未完全阐明。本研究从基因表达综合数据库（Gene Expression Omnibus database）中获取了BPH、CaP及CRPC的单细胞RNA测序（Single-cell RNA sequencing）、bulk转录组测序（bulk-RNA sequencing）及微阵列数据，并开展了全面的整合分析。通过加权基因共表达网络分析（Weighted Gene Co-Expression Network Analysis, WGCNA）与LASSO回归分析（lasso regression analysis），挖掘潜在的疾病生物标志物。经WGCNA分析，分别在BPH、CaP及CRPC样本中筛选出5个、2个及3个关键模块。通路富集分析结果显示，表观遗传与染色体相关信号通路主要富集于CaP组，而BPH与CRPC组未呈现此类富集特征。进一步通过LASSO回归分析，对BPH关键模块与CRPC关键模块的共有基因进行筛选，最终确定DDA1、ERG28、OGFOD1及OXA1L这四个基因，其转录组特征与BPH及CRPC均显著相关。更为重要的是，本研究在两个独立的抗PD-1免疫治疗队列（anti-PD-1 immunotherapy cohort）中验证了这四个基因特征的临床价值。本研究揭示了BPH与CRPC之间共有的基因特征及免疫微环境（immune microenvironment）特征。所鉴定的核心基因包括DDA1、ERG28、OGFOD1及OXA1L，有望成为前列腺癌免疫治疗的潜在治疗靶点。