Lin Lede, Li Zhen, Chen Kai, Shao Yanxiang, Li Xiang
Department of Urology and Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Urology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
Geroscience. 2025 Mar 29. doi: 10.1007/s11357-025-01623-8.
Given that hereditary prostate cancer (PCa) accounts for only a small fraction of PCa phenotypes, there is still a substantial journey ahead in exploring the somatic genetic drivers contributing to sporadic PCa. The expression quantitative trait loci (eQTLs) data were sourced from the GTEx dataset for prostate-specific genes, and the summary statistic information was collected for 5854 genes. Genetic associations with PCa were extracted from three well-established consortiums: the UK Biobank (9131 cases and 173,493 controls), the PRACTICAL study (79,148 cases and 61,106 controls), and the FinnGen cohort (13,216 cases and 119,948 controls). To prioritize potential causal targets, additional analysis, including the protein-protein interaction (PPI), The Cancer Genome Atlas (TCGA) dataset, and the single-cell-type expression analysis, was performed. Generally, a total of 150 common significant genes with the same causal association with PCa were identified. Out of the 150 genes examined, 67.33% (101/150) were found to have protein-coding functions, while only 30.67% (46/150) of these genes had prior mentions in the scientific literature. Notably, the analysis of the TCGA dataset showed that only 44.67% (67/150) of the genes produced consistent results with the Mendelian randomization (MR) analysis. Furthermore, the evaluation of single-cell RNA-seq data and colocalization analysis singled out MSMB as a critical gene associated with the occurrence of PCa. We pinpointed a range of prostate-specific genes that display causal associations with the onset of PCa. Among these, the MSMB gene emerged as a pivotal factor linked to PCa, demonstrating robust consistency across all four assessments, including the MR, TCGA dataset, single-cell RNA-seq data, and colocalization analysis. These findings provided fresh perspectives on the pathogenesis of PCa and presented potential targets for drug development.
鉴于遗传性前列腺癌（PCa）仅占前列腺癌表型的一小部分，在探索导致散发性前列腺癌的体细胞遗传驱动因素方面仍有很长的路要走。表达数量性状基因座（eQTL）数据来自GTEx数据集中的前列腺特异性基因，汇总统计信息收集了5854个基因。与前列腺癌的遗传关联从三个成熟的联盟中提取：英国生物银行（9131例病例和173493例对照）、PRACTICAL研究（79148例病例和61106例对照）以及芬兰基因队列（13216例病例和119948例对照）。为了确定潜在的因果靶点，进行了包括蛋白质-蛋白质相互作用（PPI）、癌症基因组图谱（TCGA）数据集和单细胞类型表达分析在内的额外分析。一般来说，共鉴定出150个与前列腺癌具有相同因果关联的常见显著基因。在检测的150个基因中，67.33%（101/150）被发现具有蛋白质编码功能，而这些基因中只有30.67%（46/150）在科学文献中曾被提及。值得注意的是，对TCGA数据集的分析表明，只有44.67%（67/150）的基因与孟德尔随机化（MR）分析产生一致结果。此外，对单细胞RNA测序数据的评估和共定位分析确定MSMB是与前列腺癌发生相关的关键基因。我们确定了一系列与前列腺癌发病具有因果关联的前列腺特异性基因。其中，MSMB基因成为与前列腺癌相关的关键因素，在包括MR、TCGA数据集、单细胞RNA测序数据和共定位分析在内的所有四项评估中都表现出很强的一致性。这些发现为前列腺癌的发病机制提供了新的视角，并为药物开发提供了潜在靶点。
