摘要目的:利用生物信息学分析钾通道四聚结构域17(KCTD17)在肾透明细胞癌(ccRCC)中的表达及临床意义，并探究相关机制。方法:结合癌症基因图谱数据库，分析KCTD17在ccRCC肿瘤和癌旁组织中转录水平差异及其与临床病理特征相关性。通过Kaplan-Meier和Cox回归分析KCTD17表达与ccRCC总体生存期和无进展生存期的临床关系。利用通路分析KCTD17在ccRCC中参与的机制。CIBERSORT数据库分析KCTD17表达与免疫细胞浸润及免疫检查点基因的相关性。结果:KCTD17在ccRCC癌组织中表达升高(癌比癌旁组织为3.08±0.89比2.49±0.87， t＝4.034， P<0.001)，其表达与临床分期(Ⅲ期比Ⅰ期为3.220±0.888比2.998±0.897， t＝2.298， P＝0.01，Ⅲ期比Ⅱ期为3.220±0.888比2.724±1.348， t＝2.539， P<0.05，Ⅳ期比Ⅰ期为3.402±0.832比2.998±0.897， t＝3.755， P＝0.001，Ⅳ期比Ⅱ期为3.402±0.832比2.724±1.348， t＝3.371， P<0.01)、分级(G4比G1为3.678±0.67比3.237±0.454， t＝3.058， P＝0.007；G4比G2为3.678±0.67比2.922±0.943， t＝7.572， P<0.001；G4比G3为3.678±0.67比3.102±0.920， t＝5.716， P<0.001)、肿瘤分期(T3期比T1期为3.283±0.857比3.008±0.896， t＝3.271， P<0.001；T3期比T2期为3.283±0.857比2.767±1.264， t＝3.127， P<0.01；T4期比T1期为3.925±0.997比3.008±0.896， t＝2.865， P<0.05；T4期比T2期为3.925±0.997比2.767±1.264， t＝3.308， P<0.01)、淋巴结转移(转移比非转移为4.018±0.593比3.054±1.027， t＝5.777， P<0.001)和远处转移(转移比非转移为3.375±0.791比3.027±0.979， t＝3.408， P<0.01)显著正相关。KCTD17高表达患者总体生存率( P<0.01)和无进展生存率( P<0.001)均低于低表达患者，且KCTD17是ccRCC患者总体生存期[风险比( HR)：1.408，95%可信区间( CI)：1.162~1.705， P<0.001]和无进展生存期( HR：1.609，95% CI：1.308~1.980， P<0.001)的独立预测因素。通路分析显示KCTD17可能通过上皮间质转化( P<0.001)、凝血( P<0.001)、缺氧( P<0.001)、补体( P<0.001)、白细胞介素(IL)-6/酪氨酸激酶(JAK)/信号转导与转录激活因子3(STAT3)信号( P<0.005)及脂肪酸代谢( P<0.05)及肿瘤免疫微环境相关通路[免疫反应调节( P<0.001)、淋巴细胞活化正向调节( P<0.001)、B细胞受体信号调节( P<0.001)、免疫效应过程调节( P<0.001)、补体激活调节( P<0.001)、经典补体激活途径( P<0.001)和免疫球蛋白受体结合( P<0.001)]参与ccRCC发生发展及导致不良预后。KCTD17高表达组的浆细胞(高表达组比低表达组为0.029±0.020比0.026±0.025， t＝1.702， P<0.05)、CD8 T细胞(高表达组比低表达组为0.116±0.102比0.085±0.082， t＝3.806， P<0.001)、休眠记忆CD4 T细胞(高表达组比低表达组为0.079±0.059比0.063±0.048， t＝3.357， P＝0.001)、激活记忆CD4 T细胞(高表达组比低表达组为0.006±0.002比0.004±0.003， t＝9.023， P<0.001)、滤泡辅助性T细胞(高表达组比低表达组为0.019±0.014比0.015±0.013， t＝3.409， P<0.001)、调节性T细胞(高表达组比低表达组为0.012±0.010比0.009±0.006， t＝4.191， P<0.001)、休眠NK细胞(高表达组比低表达组为0.013±0.004比0.010±0.002， t＝10.930， P<0.05)、激活NK细胞(高表达组比低表达组为0.033±0.025比0.027±0.020， t＝2.732， P<0.05)、M0巨噬细胞(高表达组比低表达组为0.023±0.012比0.016±0.010， t＝7.297， P<0.001)、M1巨噬细胞(高表达组比低表达组为0.040±0.029比0.030±0.022， t＝4.742， P<0.001)、M2巨噬细胞的浸润(高表达组比低表达组为0.207±0.100比0.155±0.082， t＝6.542， P<0.001)丰度升高。KCTD17表达水平与常见免疫检查点基因PD1[相关系数(cor)＝0.404， P<0.001]、TIGIT(cor＝0.403， P<0.001)、CTLA4(cor＝0.398， P<0.001)、LAG3(cor＝0.397， P<0.001)、MIF(cor＝0.169， P<0.001)显著正相关。 结论:KCTD17在ccRCC中高表达并提示预后不佳，可能与肿瘤微环境免疫抑制相关。

abstractsObjective:To investigate the expression and clinical significance of potassium channel tetramerization domain containing 17 (KCTD17) in clear cell renal cell carcinoma (ccRCC) and its potential role by bioinformatics.Methods:The expression of KCTD17 in ccRCC and adjacent renal tissues (ART) and its correlation with clinicopathological features were explored leveraging The Cancer Genome Atlas (TCGA). Kaplan-Meier survival analysis and Cox regression analysis were performed to discover the relation between KCTD17 and prognosis of ccRCC patients. Enrichment analysis was used to detect the potential pathways related to KCTD17 in ccRCC. CIBERSORT was utilized to analyze the correlation between KCTD17 and immune infiltration and immune checkpoint.Results:KCTD17 is up-regulated in ccRCC (ccRCC vs. ART: 3.08±0.89 vs. 2.49±0.87, t=4.034, P<0.001), and is significantly correlated with clinical stage (Stage Ⅲ vs. Stage Ⅰ: 3.220±0.888 vs. 2.998±0.897, t=2.298, P=0.01; Stage Ⅲ vs. Stage Ⅱ: 3.220±0.888 vs. 2.724±1.348, t=2.539, P<0.05; Stage Ⅳ vs. Stage Ⅰ: 3.402±0.832 vs. 2.998±0.897, t=3.755, P=0.001; Stage Ⅳ vs. Stage Ⅱ: 3.402±0.832 vs. 2.724±1.348, t=3.371, P<0.01), grade (G4 vs. G1: 3.678±0.67 vs. 3.237±0.454, t=3.058, P<0.01; G4 vs. G2: 3.678±0.67 vs. 2.922±0.943, t=7.572, P<0.001; G4 vs. G3: 3.678±0.67 vs. 3.102±0.920, t=5.716, P<0.001), tumor stage (T3 vs. T1: 3.283±0.857 vs. 3.008±0.896, t=3.271, P<0.001; T3 vs. T2: 3.283±0.857 vs. 2.767±1.264, t=3.127, P<0.01; T4 vs. T1: 3.925±0.997 vs. 3.008±0.896, t=2.865, P<0.05; T4 vs. T2: 3.925±0.997 vs. 2.767±1.264, t=3.308, P<0.01), lymph node metastasis (metastasis vs. non metastasis: 4.018±0.593 vs. 3.054±1.027, t=5.777, P<0.001) and distant metastasis (metastasis vs. non metastasis: 3.375±0.791 vs. 3.027±0.979, t=3.408, P<0.01). The overall survival ( P<0.01) and progression-free survival ( P<0.001) of patients with high KCTD17 expression were lower, and KCTD17 was an independent predictor of overall survival [hazard ratio ( HR): 1.408, 95% confidence interval ( CI): 1.162-1.705, P<0.001] and progression-free survival ( HR: 1.609, 95% CI: 1.308-1.980, P<0.001) of patients. KCTD17 may be involved in the occurrence and development of ccRCC and lead to poor prognosis through epithelial-mesenchymal transition ( P<0.001), coagulation ( P<0.001), hypoxia ( P<0.001), complement ( P<0.01), interleukin (IL)-6/janus kinase (JAK)/signal transducer and activators of transcription 3 (STAT3) signaling ( P<0.05), fatty acid metabolism ( P<0.05) and tumor immune microenvironment related pathways [regulation of immune response ( P<0.001), positive regulation of lymphocyte activation ( P<0.001), B cell receptor signaling pathway ( P<0.001), regulation of immune effector process ( P<0.001), regulation of complement activation ( P<0.001), classical complement activation, pathway ( P<0.001) and immunoglobulin receptor binding ( P<0.001)]. In addition, high expression of KCTD17 can increase the proportion of plasma cells (high expression group vs. low expression group: 0.029±0.020 vs. 0.026±0.025, t=1.702, P<0.05), CD8 T cells (high expression group vs. low expression group: 0.116±0.102 vs. 0.085±0.082, t=3.806, P<0.001), dormant memory CD4 T cells (high expression group vs. low expression group: 0.079±0.059 vs. 0.063±0.048, t=3.357, P=0.001), activated memory CD4 T cells (high expression group vs. low expression group: 0.006±0.002 vs. 0.004±0.003, t=9.023, P<0.001), follicular helper T cells (high expression group vs. low expression group: 0.019±0.014 vs. 0.015±0.013, t=3.409, P<0.001), regulatory T cells (high expression group vs. low expression group: 0.012±0.010 vs. 0.009±0.006, t=4.191, P<0.001), dormant NK cells (high expression group vs. low expression group: 0.013±0.004 vs. 0.010±0.002, t=10.930, P<0.05), activated NK cells (high expression group vs. low expression group: 0.033±0.025 vs. 0.027±0.020, t=2.732, P<0.05), M0 macrophages (high expression group vs. low expression group: 0.023±0.012 vs. 0.016±0.010, t=7.297, P<0.001), M1 macrophages (high expression group vs. low expression group: 0.040±0.029 vs. 0.030±0.022, t=4.74, P<0.001), and M2 macrophages (high expression group vs. low expression group: 0.207±0.100 vs. 0.155±0.082, t=6.542, P<0.001). Finally, the expression level of KCTD17 was significantly positively correlated with common immune checkpoint genes, e. g. , PD1 [correlation coefficient (cor)=0.404, P<0.001), TIGIT (cor=0.403, P<0.001), CTLA4 (cor=0.398, P<0.001), LAG3 (cor=0.397, P<0.001) and MIF (cor=0.169, P<0.001). Conclusion:KCTD17 is highly expressed in ccRCC and indicates poor prognosis, which may be related to immunosuppression of tumor microenvironment.