Chen Dong, Maruschke Matthias, Hakenberg Oliver, Zimmermann Wolfgang, Stief Christian G, Buchner Alexander
Department of Urology, Campus Grosshadern, Ludwig-Maximilians-University, Munich, Germany; Department of Urology, Sun-Yat-sen University Cancer Center, Guangzhou, China.
Department of Urology, University of Rostock, Rostock, Germany; Department of Urology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany.
Urology. 2017 Apr;102:265.e1-265.e7. doi: 10.1016/j.urology.2016.12.050. Epub 2017 Jan 6.
To identify and validate novel prognostic marker genes in clear cell renal cell carcinoma (RCC) that are increasingly expressed during tumor progression.
Total RNA was isolated from normal renal tissue, primary G1 and G3 tumors, 14 samples each, and 32 metastases from RCC patients. Expression profiles were created using oligonucleotide microarrays. Significant gene expression differences (P < .05) were identified among normal kidney, primary tumor, and metastases. For all filtered genes, univariate survival analysis was carried out. Genes for which lower expression was significantly associated with longer survival were further analyzed using multivariate analysis. Expression of the best candidate markers was further validated in an independent cohort of 55 primary tumors using quantitative real-time polymerase chain reaction.
Fifty-nine genes exhibited increased expression in primary RCC compared with normal kidney, and in metastases compared with primary tumors. In univariate or multivariate survival analysis, upregulation of 15 genes was significant. Expression of 8 genes was validated by quantitative real-time polymerase chain reaction. Survival analysis in an independent cohort of 55 RCC patients based on expression in primary RCC showed that TOP2A (hazard ratio [HR] = 4.3, P = .005), HELLS (HR = 3.7, P = .007), ATAD2 (HR = 3.7, P = .019), and TET3 (HR = 2.8, P = .035) represent independent predictors for cancer-specific survival. The proteins encoded by these genes function as topoisomerase, helicase, chromatin modifier, and methyl cytosine dioxygenase, respectively. They are involved in proliferation, transcription, and epigenetic modification.
High mRNA levels of TOP2A, HELLS, ATAD2, and TET3 are independent predictors of poor outcome in RCC patients and may be used for individual risk-adapted therapy in the future.
鉴定并验证在透明细胞肾细胞癌（RCC）中随肿瘤进展表达逐渐增加的新型预后标志物基因。
从正常肾组织、原发性G1和G3肿瘤（各14个样本）以及RCC患者的32个转移灶中分离总RNA。使用寡核苷酸微阵列创建表达谱。在正常肾、原发性肿瘤和转移灶之间鉴定出显著的基因表达差异（P < 0.05）。对所有筛选出的基因进行单变量生存分析。对那些表达降低与生存期延长显著相关的基因，进一步进行多变量分析。使用定量实时聚合酶链反应在55个原发性肿瘤的独立队列中进一步验证最佳候选标志物的表达。
与正常肾相比，59个基因在原发性RCC中表达增加，与原发性肿瘤相比，在转移灶中表达增加。在单变量或多变量生存分析中，15个基因的上调具有显著性。通过定量实时聚合酶链反应验证了8个基因的表达。基于原发性RCC中的表达，在55例RCC患者的独立队列中进行生存分析显示，TOP2A（风险比[HR] = 4.3，P = 0.005）、HELLS（HR = 3.7，P = 0.007）、ATAD2（HR = 3.7，P = 0.019）和TET3（HR = 2.8，P = 0.035）是癌症特异性生存的独立预测因子。这些基因编码的蛋白质分别作为拓扑异构酶、解旋酶、染色质修饰剂和甲基胞嘧啶双加氧酶发挥作用。它们参与增殖、转录和表观遗传修饰。
TOP2A、HELLS、ATAD2和TET3的高mRNA水平是RCC患者预后不良的独立预测因子，未来可能用于个性化风险适应性治疗。
