TOP2A, HELLS, ATAD2, and TET3 Are Novel Prognostic Markers in Renal Cell Carcinoma
TOP2A, HELLS, ATAD2, and TET3 Are Novel Prognostic Markers in Renal Cell Carcinoma
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DOI：
10.1016/j.urology.2016.12.050
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发表时间：
2017-04-01
期刊：
影响因子：
2.1
通讯作者：
Buchner, Alexander
中科院分区：
文献类型：
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作者：
Chen, Dong;Maruschke, Matthias;Buchner, Alexander
目的鉴定和验证透明细胞肾细胞癌（RCC）中在肿瘤进展过程中表达增加的新型预后标记基因。方法从正常肾组织、原发性G1和G3肿瘤各14例、转移性肾细胞癌32例中分离总RNA。使用寡核苷酸微阵列创建表达谱。在正常肾脏、原发肿瘤和转移瘤中，基因表达差异显著（P < 0.05）。对所有筛选后的基因进行单因素生存分析。使用多变量分析进一步分析低表达与较长生存期显著相关的基因。在55个原发肿瘤的独立队列中，使用定量实时聚合酶链反应进一步验证了最佳候选标记物的表达。结果：59个基因在原发性肾细胞癌中与正常肾脏相比表达增加，在转移性肿瘤中与原发性肿瘤相比表达增加。在单因素或多因素生存分析中，15个基因的上调是显著的。通过实时定量聚合酶链反应验证8个基因的表达。基于原发性RCC表达的55例RCC患者的独立队列生存分析显示，TOP2A（风险比[HR] = 4.3, P = 0.005）、HELLS（风险比[HR] = 3.7, P = 0.007）、ATAD2（风险比[HR] = 3.7, P = 0.019）和TET3（风险比[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具有拓扑异构酶、解旋酶、染色质修饰剂和甲基胞嘧啶双加氧酶的功能。它们参与增殖、转录和表观遗传修饰。结论高mRNA水平的TOP2A、HELLS、ATAD2和TET3是RCC患者预后不良的独立预测因子，可能在未来用于个体风险适应治疗。(C) 2017爱思唯尔公司
OBJECTIVE To identify and validate novel prognostic marker genes in clear cell renal cell carcinoma (RCC) that are increasingly expressed during tumor progression.METHODS 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.RESULTS 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.CONCLUSION 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. (C) 2017 Elsevier Inc.