Nallandhighal Srinivas, Vince Randy, Karim Razeen, Groves Skylar, Stangl-Kremser Judith, Russell Christopher, Hu Kevin, Pham Trinh, Cani Andi K, Liu Chia-Jen, Zaslavsky Alexander, Mehra Rohit, Cieslik Marcin, Morgan Todd M, Palapattu Ganesh S, Udager Aaron M, Salami Simpa S
Department of Urology, Michigan Medicine, Ann Arbor, MI, USA.
Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; Norfolk State University, Norfolk, VA, USA.
Eur Urol Oncol. 2022 Feb;5(1):92-99. doi: 10.1016/j.euo.2021.10.007. Epub 2021 Nov 26.
There is an ongoing need to develop prognostic biomarkers to improve the management of clear cell renal cell carcinoma (ccRCC).
To leverage enriched pathways in ccRCC to improve risk-stratification.
DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified two complementary discovery cohorts of patients with ccRCC who underwent (1) radical nephrectomy (RNx) with inferior vena cava tumor thrombectomy (patients = 5, samples = 24) and (2) RNx for localized disease and developed recurrence versus no recurrence (n = 36). Patients with localized ccRCC (M0) in The Cancer Genome Atlas (TCGA, n = 386) were used for validation.
A differential expression gene (DEG) analysis was performed on targeted RNA next-generation sequencing data from both discovery cohorts. Using TCGA for validation, Kaplan-Meier survival analysis and multivariable Cox proportional hazard testing were utilized to investigate the prognostic impact of DEGs, cell cycle proliferation (CCP), and a novel epithelial-mesenchymal transition (EMT) score on progression-free (PFS) and disease-specific (DSS) survival.
In the discovery cohorts, we observed overexpression of WT1 and CCP genes in the tumor thrombus versus the primary tumor, as well as in patients with recurrence versus those without recurrence. A hallmark pathway analysis demonstrated enrichment of the EMT- and CCP-related pathways in patients with high WT1 expression in the TCGA (validation) ccRCC cohort. CCP and EMT scores were derived in the validation cohort, which was stratified into four risk groups using Youden Index cut points: CCP/EMT, CCP/EMT, CCP/EMT, and CCP/EMT. The CCP/EMT risk group was associated with the worst PFS and DSS (both p < 0.001). In a multivariable analysis, CCP/EMT was independently associated with poor PFS and DSS (hazard ratio = 4.6 and 10.3, respectively; p < 0.001).
We demonstrate the synergistic prognostic impact of EMT in tumors with a high CCP score. Our novel EMT score has the potential to improve risk stratification and provide potential novel therapeutic targets.
Genes involved in epithelial-mesenchymal transition provides important prognostic information for patients with clear cell renal cell carcinoma.
持续需要开发预后生物标志物以改善透明细胞肾细胞癌（ccRCC）的管理。
利用ccRCC中富集的通路来改善风险分层。
设计、设置和参与者：我们回顾性地确定了两个互补的ccRCC患者发现队列，这些患者接受了（1）根治性肾切除术（RNx）并伴有下腔静脉肿瘤血栓切除术（患者 = 5，样本 = 24），以及（2）针对局限性疾病的RNx，并出现复发与未复发情况（n = 36）。癌症基因组图谱（TCGA，n = 386）中局限性ccRCC（M0）患者用于验证。
对来自两个发现队列的靶向RNA下一代测序数据进行差异表达基因（DEG）分析。使用TCGA进行验证，采用Kaplan-Meier生存分析和多变量Cox比例风险测试来研究DEG、细胞周期增殖（CCP）和一种新的上皮-间质转化（EMT）评分对无进展生存期（PFS）和疾病特异性生存期（DSS）的预后影响。
在发现队列中，我们观察到WT1和CCP基因在肿瘤血栓中相对于原发性肿瘤有过表达，在复发患者相对于未复发患者中也有过表达。一项标志性通路分析表明，在TCGA（验证）ccRCC队列中，WT1高表达患者的EMT和CCP相关通路富集。在验证队列中得出CCP和EMT评分，使用约登指数切点将其分为四个风险组：CCP/EMT、CCP/EMT、CCP/EMT和CCP/EMT。CCP/EMT风险组与最差的PFS和DSS相关（均p < 0.001）。在多变量分析中，CCP/EMT与不良的PFS和DSS独立相关（风险比分别为4.6和10.3；p < 0.001）。
我们证明了EMT在具有高CCP评分的肿瘤中的协同预后影响。我们新的EMT评分有潜力改善风险分层并提供潜在的新治疗靶点。
参与上皮-间质转化的基因可为透明细胞肾细胞癌患者提供重要的预后信息。
