PO.CL12.02 · 临床研究
多队列转录组分析鉴定驱动前列腺癌高危生化复发的通路
Multi-cohort transcriptomic profiling identifies pathways driving high-risk biochemical recurrence in prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：局限性或局部晚期前列腺腺癌根治性前列腺切除术后的生化复发（BCR）在临床上具有异质性，而当前的风险类别仅部分捕捉到潜在的生物学。多队列转录组整合可能阐明欧洲泌尿外科学会（EAU）低危与高危BCR之间的分子区别。目的：在独立数据集中鉴定与高危BCR相关的可重复的基因表达谱，并确定低危BCR肿瘤在生物学上是否与非复发疾病不同。方法：分析了来自TCGA-PRAD（n=479）、GSE220095（BCR-No=101，BCR-EAU-Low=45，BCR-EAU-High=30）、GSE70768（No=93，Low=7，High=12）、GSE54460（No=48，Low=29，High=21）和GSE70769（No=49，Low=21，High=24）的转录组数据。各队列被重新分类并适配为类EAU的BCR组。RNA-seq数据进行对数转换。随后对所有矩阵进行协调、过滤，并与经整理的元数据对齐。使用R软件上的limma进行差异表达分析，对比为High-vs-No、High-vs-Low和Low-vs-No。使用预排序GSEA（GO/Reactome）评估通路富集。结果：在各队列中，高危BCR肿瘤一致上调细胞周期和DNA复制程序，包括G2/M检查点激活、姐妹染色单体分离、复制应激信号和有丝分裂纺锤体组装。TCGA-PRAD高危肿瘤显示ATR依赖性复制应激通路的强烈激活。GSE220095高危病例表现出有丝分裂检查点和复制前复合体组装机制的富集。在GSE70768中，关键差异表达基因包括PAGE4、PGM5、SERPINA3和TOP2A，提示雄激素调节的应激反应程序丧失和增殖驱动增强。GSE70769和GSE54460同样汇聚于细胞周期失调、染色质重塑和ECM/EMT相关信号。低危与高危BCR组之间缺乏差异表达基因（DEGs）—尽管高危与无BCR之间存在显著差异—提示低危肿瘤形成一种异质性的中间状态，与无BCR病例共享基线表达，同时缺乏增殖和复制应激程序。计算工作流程和写作支持由基于AI的语言（ChatGPT，OpenAI）提供。结论：高危BCR肿瘤显示出由复制应激和增殖通路驱动的强烈、可重复的转录特征，而低危BCR肿瘤在分子上与非复发疾病相似。这些结果为EAU风险分层系统提供了生物学验证，并凸显了转录组分析在细化前列腺切除术后监测和治疗决策方面的潜力。
查看英文原文 English abstract
Background: Biochemical recurrence (BCR) after radical prostatectomy for localized or locally advanced prostate adenocarcinoma is clinically heterogeneous, and current risk categories only partially capture the underlying biology. Multi-cohort transcriptomic integration may clarify molecular distinctions between European Association of Urology (EAU) low- versus high-risk BCR. Objective: To identify reproducible gene-expression profile associated with high-risk BCR across independent datasets and to determine whether low-risk BCR tumors differ biologically from non-recurrent disease. Methods: Transcriptomic data were analyzed from TCGA-PRAD (n=479), GSE220095 (BCR-No=101, BCR-EAU-Low=45, BCR-EAU-High=30), GSE70768 (No=93, Low=7, High=12), GSE54460 (No=48, Low=29, High=21), and GSE70769 (No=49, Low=21, High=24). Cohorts were reclassified into and adapted EAU-like BCR groups. RNA-seq data were log-transformed. All matrices were then harmonized, filtered, and aligned to curated metadata. Differential expression was performed with limma on R software using contrasts High-vs-No, High-vs-Low, and Low-vs-No. Pathway enrichment was evaluated using preranked GSEA (GO/Reactome). Results: Across cohorts, high-risk BCR tumors consistently upregulated cell-cycle and DNA-replication programs, including G2/M checkpoint activation, sister chromatid segregation, replication-stress signaling, and mitotic spindle assembly. TCGA-PRAD high-risk tumors showed strong activation of ATR-dependent replication-stress pathways. GSE220095 high-risk cases exhibited enrichment of mitotic checkpoint and pre-replicative complex assembly mechanisms. In GSE70768, key differentially expressed genes included PAGE4, PGM5, SERPINA3, and TOP2A , indicating loss of androgen-regulated stress-response programs and increased proliferative drive. GSE70769 and GSE54460 similarly converged on cell-cycle deregulation, chromatin remodeling, and ECM/EMT-related signaling. The absence of DEGs between low- and high-risk BCR groups-despite marked differences between high-risk and No-BCR-suggests that low-risk tumors form a heterogeneous intermediate state, sharing baseline expression with No-BCR cases while lacking the proliferative and replication-stress programs. Computational workflow and writing support was provided by an AI-based language (ChatGPT, OpenAI). Conclusions: High-risk BCR tumors show a strong, reproducible transcriptional signature driven by replication stress and proliferative pathways, whereas low-risk BCR tumors are molecularly similar to non-recurrent diseases. These results provide biological validation of the EAU risk stratification system and highlight the potential of transcriptomic profiling to refine surveillance and treatment decisions after prostatectomy.
利益披露 Disclosure
S. Yepes-Rodriguez, None..
R. Parra-Medina, None.